The antigens of the ABO system (A, B, and H determinants, respectively) consist of complex carbohydrate molecules. It has been known for nearly half a century that the ABO blood group exerts a major influence on plasma levels of the von Willebrand factor (VWF)-factor VIII (FVIII) complex and that normal group O individuals have significantly lower levels of VWF and FVIII than do non-O individuals. As a consequence, several investigators have studied the association between ABO blood group and the risk of developing bleeding or thrombotic events. A number of epidemiological studies have also analyzed the biologic relevance of this interaction by assessing whether the ABO blood group could influence human longevity through the regulation of VWF-FVIII plasma levels. In this review, the molecular mechanisms by which the ABO blood group determines plasma VWF and consequently, FVIII levels, the possible clinical implications, and the current knowledge on the association between the ABO blood group and the risk of developing certain cancers will be reviewed.