The Italian War of 1551-59 was the final chapter of the Italian Wars, fought between an alliance of France, Siena, and the Ottoman Empire on one side, and an alliance of the Holy Roman Empire, Spain, Mantua, England, Florence, and Savoy on the other side. The war ended with France being forced to renounce its claim in Italy, Siena being conquered by the Duchy of Florence, and Spain acquiring Franche-Comte in Burgundy, but France won the three bishoprics of Metz, Toul, and Verdun in Lorraine, as well as the English-held port of Calais.
Following in the footsteps of his late father, King Francis I, King Henry II of France renewed the alliance with Sultan Suleiman the Magnificent, agreeing to cooperate against the Habsburgs in the Mediterranean. In 1551, remaining loyal to his alliance with the Ottomans, Henry sent the galleys of Marseille to assist the Ottomans in the reconquest of Tripoli from the Knights of St. John. In 1552, King Henry declared war on Emperor Charles V of the Holy Roman Empire and Spain, and the Ottomans sent 100 galleys to raid the coast of Calabria in southern Italy. At Ponza in 1552, Turgut Reis' Ottoman fleet destroyed Andrea Doria's Genoese fleet, and the Ottomans conquered Reggio. The Ottomans would continue to harass the anti-French alliance in the Mediterranean, invading the Balearic Islands in 1558.
Concurrently, King Henry II launched an offensive against the Habsburg on the continent. Having allied with the German Protestant princes at the 1552 Treaty of Chambord, King Henry invaded Lorraine, and he captured the three episcopal cities of Metz, Toul, and Verdun; in 1554, he confirmed these conquests by defeating the Habsburgs at Renty. In 1553, France invaded Tuscany to support Siena, but Gian Giacomo Medici defeated the French at Marciano in 1554. In 1555, the Duchy of Florence conquered Siena, and it eventually became a part of the Grand Duchy of Tuscany. On 5 February 1556, at Vaucelles, King Philip II of France made peace with King Henry II, and Franche-Comte was relinquished to Spain; the treaty was broken soon after. After Charles' 1556 abdication split the Habsburg empire between Philip II of Spain and Ferdinand I of Germany, the focus shifted to the Habsburg Netherlands. Philip, in conjunction with Emmanuel Philibert of Savoy, defeated the French at St. Quentin in August 1557, and England entered the war later that year. The French conquered Calais, ending the English presence in France for good, and the French proceeded to plunder the Spanish possessions in the Low Countries. By that time, the two sides had become financially exhausted; both Spain and France had to default on their debts in 1557.
On 3 April 1559, in the Treaty of Cateau-Cambresis, France restored Piedmont and Savoy to the Duchy of Savoy; Corsica was ceded to the Republic of Genoa; France gained control of Saluzzo, Calais, and the Three Bishoprics in Lorraine; Spain acquired Franche-Comte; and Spain was acknowledged as the ruler of Milan, Naples, Sicily, Sardinia, and the State of the Presidi; only Savoy and the Republic of Venice remained truly independent Italian states. The French had failed to break the Habsburg encirclement or change the balance of power in Italy, but they made some territorial acquisitions, and they were on better footing than they were at the start of the Habsburg-Valois wars in 1521.