There are significant inter-individual differences in naturally occurring antibody responses to the tumor-associated antigen cyclin B1 in healthy subjects with no history of cancer as well as in patients with multiple types of cancer, but the host genetic factors that might contribute to these differences have not been identified. The aim of the present investigation was to determine whether the variation in endogenous antibody levels to cyclin B1 in patients with prostate cancer was associated with immunoglobulin GM and KM alleles, expressed on the constant regions of γ and κ chains, respectively. We also aimed to determine whether particular Fcgamma receptor (FcγR) genotypes, which have been implicated in the immunobiology of several cancers, contribute to the magnitude of humoral immunity to cyclin B1. DNA samples from 129 Caucasian American (CA) and 76 African American (AA) patients with prostate cancer were genotyped for several GM, KM, and FcγR alleles. Plasma samples from these subjects were also characterized for IgG antibodies to cyclin B1. No significant associations were found between any genetic markers and the level of anticyclin B1 antibodies in CA patients. In AA patients, however, homozygosity for the valine allele at the FcγRIIIa locus was strongly associated with low antibody responsiveness to cyclin B1 (p = 0.0007). Since immunity to cyclin B1 has been shown to play a protective role, these results may, at least in part, explain the disproportionately higher rate of mortality in AA patients with prostate cancer.