The ABO polymorphism has long been suspected to be under balancing selection. To explore this possibility, we analyzed two datasets: (1) a set of 94 23-Kb sequences in European- and African-Americans produced by the Seattle SNPs project, and (2) a set of 814 2-Kb sequences in O alleles from seven worldwide populations. A phylogenetic analysis of the Seattle sequences showed a complex pattern in which the action of recombination and gene conversion are evident, and in which four main lineages could be individuated. The sequence patterns could be linked to the expected blood group phenotype; in particular, the main mutation giving rise to the null O allele is likely to have appeared at least three times in human evolution, giving rise to allele lineages O02, O01, and O09. However, the genealogy changes along the gene and variations of both numbers of branches and of their time depth were observed, which could result from a combined action of recombination and selection. Several neutrality tests clearly demonstrated deviations compatible with balancing selection, peaking at several locations along the gene. The time depth of the genealogy was also incompatible with neutral evolution, particularly in the region from exons 6 to 7, which codes for most of the catalytic domain.