Associations between the major histocompatibility complex (MHC) and reproductive performance have been reported in humans, mice, rats, pigs and chickens. Only the A locus of the bovine major histocompatibility complex (BoLA-A) has been well characterized, and 42 alleles of this locus have been identified in American cattle. Four studies were conducted to examine the association between alleles of the BoLA-A locus and reproductive performance. Testis size, which is an indicator of early puberty and increased fertility in young bulls, was examined in 440 yearling bulls from nine breeds with a gene substitution model that included the effects of breed, sire, age of dam and age or weight of the bull. Estimated breeding value for twinning was examined with a gene substitution model with 204 cattle from a herd with a high frequency of twinning. Fertility of potential partners having BoLA-A locus alleles in common was examined in a prospective study involving 101 pure-bred Hereford cows mated by artificial insemination to four pure-bred Hereford bulls. The effect of homozygosity on birth weight, preweaning weight gain and post-weaning weight gain was estimated in a sample of 683 calves from nine breeds; 22% of the calves were apparently homozygous and 78% were heterozygous at the BoLA-A locus. There were significant and large effects of some BoLA-A locus alleles on paired testicular volume, but the analyses on the other traits did not show significant associations. Substitution of the W6.1 allele for the W9A allele reduced paired testicular volume by 150 +/- 44 cm3. The W6.1 allele has now been shown to influence a reproductive trait, a production trait and susceptibility to an economically important disease. Selection for these traits may influence the frequency of the large number of alleles at the BoLA-A locus.