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Giovanni Pico della Mirandola and Angelo Poliziano were two of the most important humanists of the Italian Renaissance. They died suddenly in 1494 and their deaths have been for centuries a subject of debate. The exhumation of their remains offered the opportunity to study the cause of their death through a multidisciplinary research project. Anthropological analyses, together with documentary evidences, radiocarbon dating and ancient DNA analysis supported the identification of the remains attributed to Pico. Macroscopic examination did not reveal paleopathological lesions or signs related to syphilis. Heavy metals analysis, carried out on bones and mummified tissues, showed that in Pico's remains there were potentially lethal levels of arsenic, supporting the philosopher's poisoning theory reported by documentary sources. The arsenic concentrations obtained from analysis of Poliziano's remains, are probably more related to an As chronic exposure or diagenetic processes rather than poisoning.