Spleen in antiquity was considered by the Hippocratic medicine as a viscerous organ of spongy character, which could clear human body of the black bile. According to the Hippocratic doctrine of the 4 humors, black bile could cause a series of diseases. Both the anatomical position and shape of the spleen were also recognized. In the case of a splenic hardening, with simultaneous augmentation of its dimensions and dermal ulceration and/or splenic abscess, some interventions were proposed. Thus, herbal medicine, phlebotomy, and minimal surgery with local cauterization were applied for treatment, to confront a disease that was considered serious but not fatal. The Hippocratic physicians encountered various spleen diseases and among them they most probably confronted a rare splenic pathological entity, named centuries later as “Spetses syndrome,” a rare type of thalassemia of the Spetses island of Saronikos Gulf. Although the approach seems in modern terms rather primitive, the ancient Greek medico-philosophers most likely understood the significance of the spleen.