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Background: Understanding which parts of the genome have been most influenced by adaptive evolutionremains an unsolved puzzle. Some evidence suggests that selection has the greatest impact onregions of the genome that interact with other evolving genomes, including loci that areinvolved in host-parasite co-evolutionary processes. In this study, we used a populationgenetic approach to test this hypothesis by comparing DNA sequences of 30 putative immunesystem genes in the crustacean Daphnia pulex with 24 non-immune system genes. Results: In support of the hypothesis, results from a multilocus extension of the McDonald-Kreitman(MK) test indicate that immune system genes as a class have experienced more adaptiveevolution than non-immune system genes. However, not all immune system genes showevidence of adaptive evolution. Additionally, we apply single locus MK tests and calculatepopulation genetic parameters at all loci in order to characterize the mode of selection(directional versus balancing) in the genes that show the greatest deviation from neutralevolution. Conclusions: Our data are consistent with the hypothesis that immune system genes undergo more adaptiveevolution than non-immune system genes, possibly as a result of host-parasite arms races.The results of these analyses highlight several candidate loci undergoing adaptive evolutionthat could be targeted in future studies.