The Italian War of 1542-46 was a chapter of the Italian Wars that pitted King Francis I of France and his Ottoman allies against an alliance of the Holy Roman Empire, Spain, and England. The conflict was economically ruinous for the powers involved, and it had no clear result.
The cause of the war was the failure of the 1538 Treaty of Nice, which put an end to the Italian War of 1536-38. France and Emperor Charles V had conflicting claims on the Duchy of Milan, and King Francis sought to resolve the dispute by invading Italy. France declared war on the Habsburg empires in 1542, and French troops invaded the Low Countries. In 1543, the Ottomans and French sacked the port of Nice, which was then ruled by Charles' ally Charles III of Savoy; the French also defeated the Habsburgs at the Battle of Ceresole. Charles and King Henry VIII of England proceeded to invade France, and they launched a decisive offensive against the French by besieging Boulogne and Saint-Dizier. In 1544, Charles and Francis attempted to negotiate the Treaty of Crepy, under which the Duke of Orleans would marry a relative of Charles V, but the duke's death led to the war continuing. Henry refused to return Boulogne to the French as a part of the peace settlement, and he continued to fight until 1546, when France and England made peace. The war was the costliest of Francis and Henry's wars, and their deaths in 1547 left the resolution of the Italian Wars to their successors.