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The Fall of Constantinople had a profound impact on two of the most prominent Italian city-states, Venice and Genoa, both of whom were great trading and maritime powers. The Fall of Constantinople led to the collapse of Genoese influence in the Eastern Mediterranean and the loss of the city’s key ally. The loss of the Constantinople trade led to a decline in the economic fortunes of the city. Indeed, the city went into rapid decline and it was regularly in a state of near -anarchy as rival noble families battled for control in the states. So dire was the situation that by the early 16th century, under its Doge, it voluntarily submitted to the Spanish monarchy, in order to revive its economy and end the endemic violence in the city. Venice had arguably played a critical role in the decline of Byzantium when it diverted the Fourth Crusade to attack the Empire. It benefitted enormously from the capture of Byzantium by the Fourth Crusade and allowed it to develop a maritime Empire out of former Byzantine possessions. <ref>Pullan, Brian S. , History of Early Renaissance Italy (London: Lane, 1973), p. 117</ref>

Venice after the Fall of Constantinople was obliged to defend its possession such as Crete and Thessalonica, at a time when its trade was disrupted by the Turks. The city-state was to become entangled into a bitter struggle with the Ottomans in the Eastern Mediterranean and Balkans. The Venetians opposed the Turks from Cyprus to Albania and managed to inflict several defeats of the Sultans armies. However, the wars with the Ottomans was to weaken the Venetian Empire. It has been argued that the constant wars contributed to the decline of Venice over a period of decades. From the perspective of Italy, the Venetians became very preoccupied with the defense of their possessions in the Balkans and in the Aegean Sea. As Venice lost territories it sought to expand into Northern Italy and especially the Po Valley, this was one of the factors that led to a series of wars such as the Cambri War (1508-1516). The Fall of Constantinople was a decisive turning point for both Genoa and Venice, although it was not the sole reason for their long decline.<ref>Pullan, p. 20</ref>