Among some human populations, immunogenetic similarity between mates is associated with increased risk of pregnancy loss. To investigate the relationship between histocompatibility and reproductive performance in non-human primates, 128 pigtailed macaque couples were classified as ‘reproductively successful’ or ‘unsuccessful’ according to previous breeding performance. These couples were arranged into 64 triads composed of individual females, and a ‘successful’ and ‘unsuccessful’ mate. Individuals were typed for class I MHC antigens using a microcytotoxicity technique and species-specific alloantisera. Matched-pair analysis revealed that significantly more ‘unsuccessful’ couples shared MnLA-A antigens than did the matched ‘successful’ couples. Conditional matched-pair logistic regression analysis further revealed that parental sharing of MnLA-A antigens is an even more significant predictor of pregnancy wastage than is advanced maternal age. In our study population, sharing of MnLA-A antigens predicted 72% of pregnancy loss among ‘unsuccessful’ couples ( P < 0.009). Identification of histocompatibility-associated factors influencing pregnancy success could have profound clinical implications for chronic spontaneous abortion, intra-uterine growth retardation and birth defects in humans. Among captive primates, identification of MHC or MHC-linked genes affecting reproductive outcome could lead to more efficient colony management strategies as well as development of a model for understanding human immunologically-mediated reproductive failure.