Genetic variation in CD38-a putative oxytocin pathway gene-has been linked to higher oxytocin levels, empathy, and sensitive parenting, but also to more negative interpersonal outcomes (e.g., alienation from friends and family, poorer romantic relationship quality). To reconcile these seemingly contradictory findings, we drew upon the idea that CD38 variation may heighten social-emotional sensitivity and, consequently, make individuals prone to negative emotions in distressing interpersonal situations. To test this hypothesis, we performed a secondary analysis of a dataset including participants' (n = 171; 94 females) empathic concern ("sympathetic") and distress-related ("anxious") responses to an emotional video. Distress responses were higher for the CD38 rs3796863 AA/AC group vs. the CC group (p = 0.03, η2 = 0.027); however, there was no significant effect of genotype for empathic concern responses to the video or for indices of trait empathy. These findings provide preliminary evidence that, in the face of an interpersonal stressor, CD38 genetic variation may predict more self-focused, aversive emotional reactions. More broadly, this finding highlights the need to adopt a more nuanced perspective in which the influence of oxytocin system variation (assessed by oxytocin-related genetic variation) should be considered in light of the social context.