The Italian War of 1521–1526, 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. It arose from animosity over the election of Charles as Emperor in 1519–1520 and from Pope Leo X's need to ally with Charles against Martin Luther.

The Italian Wars were a series of conflicts fought between 1494 and 1559, mostly in the Italian Peninsula, but later expanding into Flanders, the Rhineland and Mediterranean Sea. The primary belligerents were the Valois kings of France, and their Habsburg opponents in the Holy Roman Empire and Spain. At different points, various Italian states participated in the war, some on both sides, with limited involvement from England and the Ottoman Empire.