Historically, allelic variations in blood group antigen (BGA) genes have been regarded as possible susceptibility factors for infectious diseases. Since host-pathogen interactions are major determinants in evolution, BGAs can be thought of as selection targets. In order to verify this hypothesis, we obtained an estimate of pathogen richness for geographic locations corresponding to 52 populations distributed worldwide; after correction for multiple tests and for variables different from selective forces, significant correlations with pathogen richness were obtained for multiple variants at 11 BGA loci out of 26. In line with this finding, we demonstrate that three BGA genes, namely CD55, CD151, and SLC14A1, have been subjected to balancing selection, a process, rare outside MHC genes, which maintains variability at a locus. Moreover, we identified a gene region immediately upstream the transcription start site of FUT2 which has undergone non-neutral evolution independently from the coding region. Finally, in the case of BSG, we describe the presence of a highly divergent haplotype clade and the possible reasons for its maintenance, including frequency-dependent balancing selection, are discussed. These data indicate that BGAs have been playing a central role in the host-pathogen arms race during human evolutionary history and no other gene category shows similar levels of widespread selection, with the only exception of loci involved in antigen recognition.