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1522–1573: Rhodes, Malta and the Holy League

Ottoman forces invaded and captured the island of Rhodes in 1522, after two previous failed attempts (see Siege of Rhodes (1522)). The Knights of Saint John were banished to Malta, which was in turn besieged in 1565.

After a siege of three months, the Ottoman army failed to control all of the Maltese forts. Delaying the Ottomans until bad weather conditions and the arrival of Sicilian reinforcements, made Ottoman commander Kızılahmedli Mustafa Pasha quit the siege. Around 22,000 to 48,000 Ottoman troops against 6,000 to 8,500 Maltese troops, the Ottomans failed to conquer Malta, sustaining more than 25,000 losses, including one of the greatest Muslim corsair generals of the time, Dragut, and were repulsed. Had Malta fallen, Sicily and mainland Italy could have fallen under the threat of an Ottoman invasion. The victory of Malta during this event, which is nowadays known as the Great Siege of Malta, turned the tide and gave Europe hopes and motivation. It also marked the importance of the Knights of Saint John and their relevant presence in Malta to aid Christendom in its defence against the Muslim conquest.

The Ottoman naval victories of this period were in the Battle of Preveza (1538) and the Battle of Djerba (1560).

The Mediterranean campaign, which lasted from 1570 to 1573, resulted in the Ottoman conquest of Cyprus. A Holy League of Venice, the Papal States, Spain, the Knights of Saint John in Malta and initially Portugal was formed against the Ottoman Empire during this period. The League's victory in the Battle of Lepanto (1571) briefly ended Ottoman predominance at sea.