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The pressure to survive relentless pathogen exposure explains the frequent observation that immune genes are among the fastest-evolving in the genomes of many taxa, but an intriguing proportion of immune genes also appear to be under purifying selection. Though variance in evolutionary signatures of immune genes is often attributed to differences in gene-specific interactions with microbes, this explanation neglects the possibility that immune genes participate in other biological processes that could pleiotropically constrain adaptive selection. In this study, we analyzed available transcriptomic and genomic data from Drosophila melanogaster and related species to test the hypothesis that there is substantial pleiotropic overlap in the developmental and immunological functions of genes involved in immune signaling and that pleiotropy would be associated with stronger signatures of evolutionary constraint. Our results suggest that pleiotropic immune genes do evolve more slowly than those having no known developmental functions, and that signatures of constraint are particularly strong for pleiotropic immune genes that are broadly expressed across life stages. However, pleiotropic immune genes also contain a significantly higher proportion of positively selected sites and substitutions are more likely to be under positive selection, suggesting a mechanism to circumvent evolutionary constraint. These results support the general yet untested hypothesis that pleiotropy can constrain immune system evolution, raising new fundamental questions about the benefits of maintaining pleiotropy in systems that need to rapidly adapt to changing …