Oxytocin, vasopressin, and their receptor genes influence prosocial behavior in the laboratory and in the context of close relationships. These peptides may also promote social engagement following threat. However, the scope of their prosocial effects is unknown. We examined oxytocin receptor (OXTR) polymorphism rs53576, as well as vasopressin receptor 1a (AVPR1a) polymorphisms rs1 and rs3 in a national sample of U.S. residents (n = 348). These polymorphisms interacted with perceived threat to predict engagement in volunteer work or charitable activities and commitment to civic duty. Specifically, greater perceived threat predicted engagement in fewer charitable activities for individuals with A/A and A/G genotypes of OXTR rs53576, but not for G/G individuals. Similarly, greater perceived threat predicted lower commitment to civic duty for individuals with one or two short alleles for AVPR1a rs1, but not for individuals with only long alleles. Oxytocin, vasopressin, and their receptor genes may significantly influence prosocial behavior and may lie at the core of the caregiving behavioral system.