Giovanni Boccaccio's fatal disease(s) and cause of death have long remained a mystery. Now, for the first time, a thorough multidisciplinary reassessment has finally been carried out. By combining philological and clinical approaches, it is at last possible to suggest a solid retrospective diagnosis based upon a study of his correspondence, poetry and iconography, as well as references to his physical decay in coeval and later sources. It would appear that he suffered over the last three years of his life from hepatic and cardiac failure, conditions that resulted in edema and potentially even hepatic carcinoma. Focusing on an unusually well-documented case from the Middle Ages, this analysis of exceptionally high informative value reconstructs the symptoms of his medical conditions and finally permits us to clarify and explain the historical feaures, presentations and evolutionary history of the case at hand.