There is some fear that Rome will suffer the same fate as Constantinople, which had fallen only twenty-seven years earlier.

Plans are made for the Pope and citizens of Rome to evacuate the city.

Pope Sixtus IV repeats his 1471 call for a crusade.

Several Italian city-states, Hungary and France respond positively to this.

The Republic of Venice does not, as it had signed an expensive peace treaty with the Ottomans in 1479.

An army is raised by king Ferdinand I of Naples to be led by his son Alphonso II of Naples, and king Matthias Corvinus of Hungary provides a contingent of troops.

The Christian forces besiege  the city on May 1, 1481, but when the Sultan of the Ottoman Empire, Mehmed II, dies on May 3 without the quarrels about his succession being finalized, the subsequent succession crisis results in the failure to send Ottoman reinforcements to relieve Otranto.

The Turkish garrison in Otranto is forced to negotiate with the Christian forces, which permit the Turks to withdraw to Albania.

The failure of the Pazzi Conspiracy against Florence in 1478 and the unexpected peace as a result of Lorenzo de' Medici's daring personal diplomacy with Ferdinand I of Naples, the Pope's erstwhile champion, is a source of discontent among the Venetians and Pope Sixtus IV alike.

Venice, having ended its long conflict with the Ottoman Turks in 1479 with the Treaty of Constantinople, is thus free to turn its complete attention to its role in its terra firma (main land) and generally to the peninsula of Italy.

In addition to the usual minor friction over strongholds along the borders, there is a contest over the commerce in salt, which is reserved to Venice by a commercial pact.

Nevertheless, Ferrara, which is ruled by Ercole I d'Este, has begun to take control over the saltworks at Comacchio.

This appears to be a threat to mainland interests of the Serenissima.

Venice is supported by Girolamo Riario, lord of Imola and Forlì,—the nephew of Pope Sixtus—who had taken possession of the strategic stronghold of Forlì in September 1480, with quick papal confirmation, and who now looks towards Ferrara in extending Della Rovere territory.

The immediate casus belli at the beginning of 1482 is a minor infraction of prerogatives: Venice had maintained a representative in Ferrara with the high title of visdominio, under whose care was the Venetian community in Este lands.

The visdominio, overreaching his mandate in 1481 with the arrest of a priest for debt, had been excommunicated by the vicar of the bishop of Ferrara, and forced out of the city.

On this excuse, war is declared.

Allied with Venice, besides the papal troops and Riario, are contingents supplied by the Republic of Genoa and William VIII, Marquis of Montferrat.

Troops taking Ferrara's side, loosely under the command of Federico da Montefeltro, duke of Urbino, are those of Ercole's father-in-law Ferdinand of Naples, under his son Alfonso of Calabria, who invaded the Papal States from the south, as well as those sent by Ludovico il Moro of Milan and by the lords of two cities threatened by the mainland power of Venice, Federico I Gonzaga of Mantua and Giovanni II Bentivoglio of Bologna.

Venetian troops led by the condottiero Roberto Sanseverino attack Ferrarese territory from the north, brutally sacking Adria, quickly overrunning Comacchio, attacking Argenta at the edge of the saltmarshes and besieging Ficarolo in May, which capitulates on June 29, and Rovigo, which capitulates on August 17.

Venetian forces cross the Po River and in November 1482 stand before the walls of Ferrara and lay strict siege to the city.

Sixtus appears to have had a change of heart at the season's advances, which now threaten o put Venice in an uncomfortably strong position in mainland northern Italy.

The Colonna family akes advantage of disorder in the Papal States to fight pitched battles against their Della Rovere enemies.

The main encounter, however, is the pitched Battle of Campomorto near Velletri, August 21, 1482, in which the Neapolitan troops under Alfonso are soundly defeated by Roberto Malatesta and the duke is barely rescued by a contingent of his Turkish soldiers.

Some Orsini castles also fall into papal hands, but where battle fails malaria succeeds: Malatesta's death in Rome on September 10 largely unravels Papal successes in the Lazio.

Sixtus makes a separate peace with Naples in a truce of November 28 and a peace treaty is signed on December 12.

The pope’s entreaties with Venice to cease hostilities are vigorously rebuffed, with threats of excommunication countered by the withdrawal of the Venetian ambassador, followed by Sixtus' interdict of Venice in May 1483.

Now Sixtus grants free passage to Alfonso and his troops to go to defend Ferrara against the pope's recent allies, aided by papal troops under Virginio Orsini.

A contingent of Florentine troops arrives also, and the fortunes of Este begin to look much better.

Venice, in a diversionary maneuver, sends Roberto Sanseverino to attack the Duchy of Milan under the pretext of supporting the rights of the Visconti heir, but the diversion is further diverted when Robert has to counter Alfonso, who is sacking Milanese territories.

The war begins to lose momentum.

Sixtus had been rendered more eager to sue for peace by the series of victories by Venetian forces, who seized the opportunity to forward their territorial ambitions and had been hasty to declare war on Ferrara on a minor pretext.

Florence, Naples, Mantua, Milan, and Bologna have stood by Ferrara.

While the papal forces were holding in check the Neapolitans who sought to move north to aid Ferrara, and with the Roman Campagna being harassed by the Colonna, and Milan engaged in combat with Genoa, the Venetians had besieged Ferrara into starvation.

With the Venetians ready to take over Ferrara, the Pope, fearing his erstwhile allies, had suddenly changed sides: he made a treaty with Naples, and permitted the Neapolitan army to pass through his territories, giving them the chance to convey supplies to Ferrara and neutralize the siege.

At the same time the Pope had excommunicated the Venetians, and now urges all Italy to make war upon them.

Venice, taking advantage of dissension among the allies arrayed against them, secretly concludes with Milan the Peace of Bagnolo on August 7 1484.

Their battle defeats notwithstanding, the Venetians retain convention rights over Ferrara and Ercole cedes the territory of Rovigo in the Polesine, lost at an early stage of the fighting.

The war comes to a conclusion with the Treaty of Bagnolo and the Venetian forces that are occupying Ferrara-owned territory withdraw.

Ercole has successfully avoided the absorption of Ferrara, seat of the Este, into the Papal States.

The Peace of Bagnolo checks Venetian expansion in the terra firma, ceding to it the town of Rovigo and a broad swath of the fertile delta of the Po.

This acquisition agreed upon at Bagnolo marks the high-point of Venetian territory; never again will Venice control so large a territory nor have so much influence as it does in the last half of the fifteenth century.

Nevertheless, Sixtus is not pleased with the terms reached without consulting him.

When the ambassadors declared to him the terms of the treaty he is thrown into a violent rage, and declares the peace to be at once shameful and humiliating.

Suffering from gout, he dies on the following day, August 12, 1484.