The Italian War of 1521-1526 was a part of the Italian Wars. The war pitted King Francis I of France and the Republic of Venice against Holy Roman Emperor Charles V, King Henry VIII of England, and the Papal States, and it was caused by animosity over the election of Emperor Charles V as Holy Roman Emperor and from Pope Leo X's need to ally with Charles against the Protestant reformer Martin Luther.
In 1519, King Charles I of Spain, a member of the German House of Habsburg, inherited the throne of the Holy Roman Empire on the death of Emperor Maximilian I. Charles' accession to the throne threatened France, which was now bordered to the north, east, and south by Habsburg possessions. In 1521, King Francis of France decided to launch a two-pronged offensive against the Habsburg threat. A Franco-Navarrese expeditionary force invaded Spain in an attempt to reconquer Navarre, while another French army advanced north into the Habsburg Netherlands. A Spanish army drove the Navarrese army back into the Pyrenees, and the French army in the Low Countries was forced to retreat, although it defeated Imperial incursions into northern France.
Pope Adrian VI, seeking to drive the distracted French from Lombardy, proceeded to ally with Charles V, as well as King Henry VIII of England, another enemy of France. It was not until 1522, after the French defeat in the Low Countries, that Italy became a major theater of the war. On 27 April 1522, at Bicocca, Imperial and Papal forces under Prospero Colonna defeated the French, who were driven from Lombardy. France's ally, the Republic of Venice, made a separate peace as the French were driven back onto their soil. In 1523, England invaded France, and Charles III, Duke of Bourbon, alienated by Francis' attempts to seize his inheritance, sided with the Imperial forces. In 1524, after the French launched a failed invasion of Italy, Bourbon led a Spanish army into Provence.
In 1525, King Francis attempted to turn the tide of the war with another invasion of northern Italy. His army met a disastrous defeat at the Battle of Pavia, in which the Imperial-Spanish troops captured Francis and killed many of his chief nobles. Francis was imprisoned in Spain, and he succeeded in allying with Sultan Suleiman the Magnificent of the Ottoman Empire from behind bars. The Ottomans invaded the Balkans and defeated Charles V's allies at the Battle of Mohacs in 1526, but King Francis was ultimately forced to make peace with Charles in exchange for his release; he also made peace with England in the Treaty of Hampton Court. Francis surrendered his claims to Italy, Flanders, and Burgundy, but he renounced this treaty a few weeks later, leading to the War of the League of Cognac.