BECAUSE of the central role of major histocompatibility complex (MHC) genes in immune recognition 1-3, it is often assumed that parasite-driven selection maintains the unprecedented genetic diversity of these genes 4-7. But associations between MHC genotype and specific infectious diseases have been difficult to identify 8,9 with a few exceptions such as Marek's disease 10 and malaria 11. Alternatively, MHC-related reproductive mechanisms such as selective abortion 12-15 and mating preferences 16,17 could be responsible for the diversity. To determine both the nature and strength of selection operating on MHC genes by we have studied components of selection in seminatural populations of mice (Mus musculus domesticus). Here we assess MHC-related patterns of reproduction and early (preweaning) mortality by analysing 1,139 progeny born in nine populations, and 662 progeny from laboratory matings. Reproductive mechanisms, primarily mating preferences, result in 27% fewer MHC-homozygous offspring than expected from random mating. MHC genotype had no detectable influence on neonatal (preweaning) mortality. These mating preferences are strong enough to account for most of the MHC genetic diversity found in natural populations of Mus.