The Italian War of 1521–1526, sometimes known as the Four Years' War, (French: Sixième guerre d'Italie) 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 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.

In 1521 Charles V and Henry VIII signed the Treaty of Bruges in secret against France, and hostilities resumed on the Italian Peninsula. 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 the French military leader Charles de Bourbon, alienated by Francis's attempts to seize his inheritance, betrayed Francis and allied himself with the Emperor. The failure of a French attempt to regain Lombardy in 1524 provided Bourbon with an opportunity to invade Provence at the head of a Spanish army.

Francis led a second attack on Milan in 1525. His disastrous defeat at the Battle of Pavia, where he was captured by the Imperial captain Charles de Lannoy and many of his chief nobles were killed, led to the end of the war. Francis was imprisoned in the Lombard city of Pizzighettone and then in Madrid. Diplomatic manoeuvres to obtain his release included a French mission sent by his mother, Louise of Savoy, to the court of Suleiman the Magnificent that resulted in an Ottoman ultimatum to Charles. This unprecedented alignment between Christian and Muslim monarchs caused a scandal in the Christian world, and laid the foundation for the Franco-Ottoman alliance. Suleiman invaded Hungary in the summer of 1526, defeating Charles' allies at the Battle of Mohács. Despite these efforts, Francis signed the Treaty of Madrid, surrendering his claims to Italy, Artois, Flanders, and Burgundy. A few weeks after his release, he repudiated the terms of the treaty, starting the War of the League of Cognac. The Italian Wars continued for another three decades, ending with France having failed to regain any substantial territories in Italy.

Following the Treaty of London (1518), the major European powers (France, England, Spain, and the Holy Roman Empire) were outwardly friendly towards each other. The treaty pledged them all to come to the aid of any signatory that was attacked, and to unite against any state that broke the peace. They were divided on the question of the Imperial succession; the Holy Roman Emperor, Maximilian I—intending for a Habsburg to succeed him—campaigned throughout 1518 on behalf of his grandson Charles I of Spain, while Francis I of France put himself forward as an alternate candidate. The Papacy and the Holy Roman Empire were forced to cooperate in dealing with the rising influence of Martin Luther, who found support among some Imperial nobles when he opened the way for them to assume authority over their local churches. At the same time, Francis was faced with Henry's able, efficient and intelligent chief advisor Cardinal Thomas Wolsey, the "power behind the throne" who interposed himself into the quarrels of the continent in an attempt to increase both England's influence and his own.

Maximilian's death on 12 January 1519 brought the Imperial election to the forefront of European politics. Pope Leo X, threatened by the presence of Spanish troops 64 kilometres (40 mi) from the Vatican, supported the French candidacy. The election was not a foregone conclusion; with the exception of Frederick of Saxony and Joachim I of Brandenburg, all the electors accepted large bribes from Charles to obtain their votes. Maximilian had already promised sums of 500,000 florins to the prince-electors in exchange for their votes, but Francis offered up to three million florins, and Charles retaliated by borrowing vast sums from the Fugger banking family. The prince-electors all eventually voted for Charles, and he was crowned King of the Romans on 23 October 1520, by which point he already controlled both the Spanish crown and the hereditary Burgundian lands in the Low Countries.

During the autumn of 1521, the English became involved in arbitrating between Spain and France. Henry entertained the emperor in Kent for three days, in a meeting that achieved little, although the Treaty of Windsor (16 June 1522) reaffirmed the alliance between England and Aragon. Henry and Francis staged an extravagant meeting at the Field of the Cloth of Gold throughout June 1520. The following month, Henry sought an agreement with Charles at Gravelines.

Charles was crowned King of the Romans at Aachen in October 1520, but not Holy Roman Emperor, which could only happen if he was crowned by the pope in Rome. To divert Charles—and his army—from entering and possibly taking control of Italy, Francis sought to wage war on the emperor by proxy, and made plans for simultaneous incursions into German and Spanish territory. Luxembourg was attacked under the leadership of Robert de la Marck, whilst a French-Navarrese army simultaneously advanced through Navarre after reconquering St-Jean-Pied-de-Port. The expedition was nominally led by the 18-year-old Navarrese king Henry d'Albret, whose kingdom had been invaded by Ferdinand II of Aragon in 1512, but the army was effectively commanded by André de Foix and funded and equipped by the French. The French plans proved to be flawed, as the intervention of Henry of Nassau drove back the Luxembourg offensive; and although de Foix was initially successful in seizing Pamplona, he was driven from Navarre after being defeated at the Battle of Esquiroz on 30 June 1521.