A Spanish force commanded by Hugo of Moncada lands near Genoa in early December, intending to interfere in a conflict between pro-Valois and pro-Habsburg factions in the city.

Francis dispatches a larger force under Michele Antonio I of Saluzzo to intercept them.

Confronted by the more numerous French and left without naval support by the arrival of a pro-Valois fleet commanded by Andrea Doria, the Spanish troops surrender.

Francis now signs a secret agreement with Pope Clement VII, who pledges not to assist Charles in exchange for Francis's assistance with the conquest of Naples.

Against the advice of his senior commanders, Francis detaches a portion of his forces under the Duke of Albany and sends them south to aid the Pope.

Lannoy attempts to intercept the expedition near Fiorenzuola, but suffers heavy casualties and is forced to return to Lodi by the intervention of the infamous Black Bands of Giovanni de' Medici, which had just entered French service.

Medici now returns to Pavia with a supply train of gunpowder and shot gathered by the Duke of Ferrara, but the French position is simultaneously weakened by the departure of nearly five thousand Grisons Swiss mercenaries, who return to their cantons in order to defend them against marauding landsknechts.

Lannoy is reinforced in January 1525 by the arrival of Georg Frundsberg with fifteen thousand fresh landsknechts and renews the offensive.

D'Avalos captures the French outpost at San Angelo, cutting the lines of communication between Pavia and Milan, while a separate column of landsknechts advances on Belgiojoso and, despite being briefly pushed back by a raid led by Medici and Bonnivet, occupies the town.

Lannoy is only a few miles from Pavia by February 2.

Francis has encamped the majority of his forces in the great walled park of Mirabello outside the city walls, placing them between Leyva's garrison and the approaching relief army.

Skirmishing and sallies by the garrison continue through the month of February.

Medici is seriously wounded and withdraws to Piacenza to recuperate, forcing Francis to recall much of the Milan garrison to offset the departure of the Black Band; but the fighting has little overall effect.

On February 21, the Imperial commanders, running low on supplies and mistakenly believing that the French forces are more numerous than their own, decide to launch an attack on Mirabello Castle in order to save face and demoralize the French sufficiently to ensure a safe withdrawal.

Imperial engineers open breaches in the walls of Mirabello in the early morning of February 24, 1525, allowing Lannoy's forces to enter the park.

At the same time, Leyva sorties from Pavia with what remains of the garrison.

In the ensuing four-hour battle, the French heavy cavalry, which had proven so effective against the Swiss at Marignano ten years prior, masks its own artillery by a rapid advance and is surrounded and cut apart by landsknechts and d'Avalos's massed Spanish arquebusiers.

Meanwhile, a series of protracted infantry engagements results in the rout of the Swiss and French infantry.

The French suffer massive casualties, losing the majority of their army.

Among those killed are Bonnivet, Jacques de la Palice, La Trémoille, and Richard de la Pole, the last member of the House of York to actively and openly seek the crown of England, while Anne de Montmorency, Robert de la Marck, and Francis himself are taken prisoner along with a host of lesser nobles.

The Vatican Library is saved because Philibert had set up his headquarters there.

After three days of ravages, Philibert orders the sack to cease, but few obey.

In the meantime, Clement remains a prisoner in Castel Sant'Angelo.

Francesco Maria della Rovere and Michele Antonio of Saluzzo arrive with troops on June 1 in Monterosi, north of the city.

Their cautious behavior prevents them from obtaining an easy victory against the now totally undisciplined Imperial troops.

On June 6, Clement VII surrenders, and agrees to pay a ransom of four hundred thousand ducati in exchange for his life; conditions include the cession of Parma, Piacenza, Civitavecchia and Modena to the Holy Roman Empire (however, only the last can be occupied in fact).

At the same time, …

…Venice takes advantage of his situation to capture Cervia and …

…Ravenna, while …

…Sigismondo Malatesta returns in Rimini.