This study examined the associations between prenatal cocaine exposure and quality of mother–infant play interactions at 13months of infant ages. We investigated whether maternal psychological distress and infant reactivity mediated or moderated this association. Participants consisted of 220 (119 cocaine exposed and 101 non-cocaine exposed) mother–infant dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that mothers who used cocaine during pregnancy displayed higher negative affect and lower sensitivity toward their infant during play interactions at 13months, and that their infants were less responsive toward them. Contrary to hypothesis, this association was not mediated by maternal psychological distress or by infant reactivity. However, results for both the cocaine and non-cocaine exposed infants were supportive of a transactional model where lower maternal sensitivity at 1month was predictive of higher infant reactivity at 7months, which in turn was predictive of lower maternal warmth/sensitivity at 13months, controlling for potential stability in maternal behavior. Results also indicated that as hypothesized, infant reactivity moderated the association between maternal cocaine use during pregnancy and maternal warmth/sensitivity at 13months of age. Cocaine-using mothers who experienced their infants as being more reactive in early infancy were less warm/sensitive toward them in later infancy. Results have implications for parenting interventions that may be targeted toward improving maternal sensitivity among cocaine-using mothers with more reactive infants.