In house mice, genetic compatibility is influenced by the t haplotype, a driving selfish genetic element with a recessive lethal allele, imposing fundamental costs on mate choice decisions. Here, we evaluate the cost of genetic incompatibility and its implication for mate choice in a wild house mice population. In laboratory reared mice, we detected no fertility (number of embryos) or fecundity (ability to conceive) costs of the t, and yet we found a high cost of genetic incompatibility: heterozygote crosses produced 40% smaller birth litter sizes because of prenatal mortality. Surprisingly, transmission of t in crosses using +/t males was influenced by female genotype, consistent with postcopulatory female choice for + sperm in +/t females. Analysis of paternity patterns in a wild population of house mice showed that +/t females were more likely than +/+ females to have offspring sired by +/+ males, and unlike +/+ females, paternity of their offspring was not influenced by +/t male frequency, further supporting mate choice for genetic compatibility. As the major histocompatibility complex (MHC) is physically linked to the t, we investigated whether females could potentially use variation at the MHC to identify male genotype at the sperm or individual level. A unique MHC haplotype is linked to the t haplotype. This MHC haplotype could allow the recognition of t and enable pre- and postcopulatory mate choice for genetic compatibility. Alternatively, the MHC itself could be the target of mate choice for genetic compatibility. We predict that mate choice for genetic compatibility will be difficult to find in many systems, as only weak fertilization biases were found despite an exceptionally high cost of genetic incompatibility.