The antigens of the ABO blood group system (A, B and H determinants) are complex carbohydrate molecules expressed on red blood cells and on a variety of other cell lines and tissues. Growing evidence is accumulating that ABO antigens, beyond their key role in transfusion medicine, may interplay with the pathogenesis of many human disorders, including infectious, cardiovascular and neoplastic diseases. In this narrative review, after succinct description of the current knowledge on the association between ABO blood groups and the most severe diseases, we aim to elucidate the particularly intriguing issue of the possible role of ABO system in successful aging. In particular, focus will be placed on studies evaluating the ABO phenotype in centenarians, the best human model of longevity.