The identification of factors affecting the susceptibility to infectious diseases is essential toward reducing their burden on the human population. The ABO blood type correlates with susceptibility to malaria and other infectious diseases. Due to the structural similarity between blood antigen B and Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal), we hypothesized that self-tolerance to antigen B affects the immune response to α-Gal, which in turn affects the susceptibility to infectious diseases caused by pathogens carrying α-Gal on their surface. Here we found that the incidence of malaria and tuberculosis, caused by pathogens with α-Gal on their surface, positively correlates with the frequency of blood type B in endemic regions. However, the incidence of dengue fever, caused by a pathogen without α-Gal, was not related to the frequency of blood type B in these populations. Furthermore, the incidence of malaria and tuberculosis was negatively correlated with the anti-α-Gal antibody protective response. These results have implications for disease control and prevention.