The human genome encodes a limited number of genes yet contribute to individual differences in a vast array of heritable traits. A possible explanation for the capacity our genome to generate this virtually unlimited range of phenotypic variation in complex traits to assume functional interactions between genes. Therefore we searched two mammalian genomes to identify potential epistatic interactions by looking for co-adapted genes marked by excess two-locus genetic differentiation between populations/lineages using publicly available SNP genotype data. The practical motivation for this effort is to reduce the number of pair-wise tests that need to be performed in genome-wide association studies aimed at detecting GxG interactions, by focusing on pairs predicted to be more likely to jointly affect variation in complex traits. Hence, this approach generates a list of candidates interactions that can be empirically tested. In both the mouse and human data we observed two-locus genetic differentiation in excess of what can be expected from chance alone based on simulations. In an attempt to validate our hypothesis that pairs of genes showing excess genetic divergence represent potential functional interactions we selected a small set of gene combinations postulated to be interacting based on our analyses and looked for a combined effect of the selected genes on variation in complex traits both mice and man. In both cases the individual effect of the genes were not significant. Instead we observed marginally significant interaction effects. These results show that genome wide searches for gene-gene interactions based on population genetic data are feasible and can generate interesting candidate gene pairs to be further tested for their contribution to phenotypic variation in complex traits. © 2008 Bochdanovits et al.