The Italian War of 1521–26, sometimes known as the Four Years' War, was a part of the Italian Wars. The war pitted 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 arose 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 broke out across Western Europe late in 1521, when a French–Navarrese expedition attempted to reconquer Navarre while a French army invaded the Low Countries. A Spanish army drove the Navarrese forces back into the Pyrenees, and other Imperial forces attacked northern France, where they were stopped in turn.
The Pope, the Emperor, and Henry VIII then signed a formal alliance against France, and hostilities resumed on the Italian Peninsula; but, with the attention of both Francis and Charles focused on the battleground in northeast France, the conflict in Italy became something of a sideshow. At the Battle of Bicocca on 27 April 1522, Imperial and Papal forces defeated the French, driving them from Lombardy. Following the battle, fighting again spilled onto French soil, while Venice made a separate peace. The English invaded France in 1523, while Charles de Bourbon, alienated by Francis's attempts to seize his inheritance, betrayed Francis and allied himself with the Emperor. A French attempt to regain Lombardy in 1524 failed and provided Bourbon with an opportunity to invade Provence at the head of a Spanish army.
Francis himself led a second attack on Milan in 1525. While he was initially successful in driving back the Spanish and Imperial forces, his disastrous defeat at the Battle of Pavia, where he was captured and many of his chief nobles were killed, led to the end of the war. With Francis imprisoned in Spain, a series of diplomatic maneuvers centered on his release ensued, including a special French mission sent by Francis' mother Louise of Savoy to the court of Suleiman the Magnificent that would result in an Ottoman ultimatum to Charles—an unprecedented alignment between Christian and Muslim monarchs that would cause a scandal in the Christian world and lay the foundation for the Franco-Ottoman alliance. Suleiman used the opportunity to invade Hungary in the summer of 1526, defeating Charles' allies at the Battle of Mohács; but, despite these efforts, Francis would sign the Treaty of Madrid, surrendering his claims to Italy, Flanders, and Burgundy. Only a few weeks after his release, however, he repudiated the terms of the treaty, starting the War of the League of Cognac. Although the Italian Wars would continue for another three decades, they would end with France having failed to regain any substantial territories in Italy.