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During early modern period Mediterranean people feared epidemics far more than war and other destructive activities. Where epidemics, especially the plague, struck, all communications broke down and trade just withered away. With the coming of the Knights of St. John in 1530 the Maltese Islands became increasingly important as an international boarding place in the very center of the Mediterranean. Soon the maritime development of the Order's state was enhanced by the high regard in which the Maltese Quarantine System was held by European countries in the 17th and 18th century. The aetiology of plague was then unknown and the restrictive measures adopted by the Maltese Quarantine System too were in accordance with the approved epidemiological practices and theories of the time. This article tries to single out the importance of the Maltese Quarantine as a kind of medical "shield" for the southern European countries.