The Italian War of 1521–26, sometimes known as the Four Years' War, pits Francis I of France and the Republic of Venice against the Holy Roman Emperor Charles V, Henry VIII of England, and the Papal States.

The conflict arises from animosity over the election of Charles as Emperor in 1519–20 and from Pope Leo X's need to ally with Charles against Martin Luther.The war breaks out across western Europe late in 1521 when the French invade Navarre and the Low Countries.

Imperial forces overcome the invasion and attack northern France, where they are stopped in turn.

The Pope, the Emperor, and Henry VIII now sign a formal alliance against France, and hostilities begin on the Italian peninsula.

At the Battle of Bicocca, Imperial and Papal forces defeat the French, driving them from Lombardy.

Following the battle, fighting again spilla onto French soil, while Venice makes a separate peace.

The English invade France in 1523, while Charles de Bourbon, alienated by Francis's attempts to seize his inheritance, betrays Francis and allies himself with the Emperor.

A French attempt to regain Lombardy in 1524 fails and provides Bourbon with an opportunity to invade Provence at the head of a Spanish army.Francis himself leads a second attack on Milan in 1525.

While he is initially successful in driving back the Spanish and Imperial forces, his disastrous defeat at the Battle of Pavia, where he is captured and many of his chief nobles were killed, leads to the end of the war.

While imprisoned in Spain, Francis signs the Treaty of Madrid, surrendering his claims to Italy, Flanders, and Burgundy.

Only a few weeks after his release, however, he repudiates the terms of the treaty, starting the War of the League of Cognac.

Although the Italian Wars will continue for another three decades, they will end with France having failed to regain any substantial territories in Italy.