Variability in oxytocin signaling is associated with individual differences in sex-specific social behavior across species. The effects of oxytocin signaling on social behavior are, in part, mediated through its modulation of amygdala function. Here we use imaging genetics to examine sex-specific effects of three single nucleotide polymorphisms in the human oxytocin receptor gene (OXTR; rs1042778, rs53576, rs2254298) on threat-related amygdala reactivity and social behavior in 406 Caucasians. Analyses revealed that among men but not women,OXTRrs1042778 TT genotype was associated with increased right amygdala reactivity to angry facial expressions, which was uniquely related to higher levels of antisocial behavior among men. Moderated meditation analysis suggested a trending indirect effect ofOXTRrs1042778 TT genotype on higher antisocial behavior, via increased right amygdala reactivity to angry facial expressions in men. Our results provide evidence linking genetic variation in oxytocin signaling to individual differences in amygdala function. The results further suggest that these pathways may be uniquely important in shaping antisocial behavior in men.