Background Prenatal alcohol exposure has been associated with deficits in many developmental areas. Effects on developmental outcomes can be exacerbated by cumulative risk across the pre-and postnatal environments. Given that the parent-infant relationship provides the primary context for healthy child development, it is possible that maternal caregiving may play a substantial role in mitigating these effects. Objectives To clarify the role of the quality of the mother-child relationship in the relation between cumulative risk and neurodevelopmental outcomes. Methods Participants were 40 infants/children and their mothers with substance-use problems who were taking part in an early mental health intervention program. Cumulative risk, across the pre-and postnatal period was measured, and quality of the mother-child relationship was rated based on clinical file reviews and observation of mother-child interactions. Outcome measures were infant/child IQ, and neurobehavioral functioning rated across several developmental domains. Results The quality of the mother-child relationship mediated the direct relation between cumulative risk and neurobehavioral functioning, and cumulative risk was related with IQ indirectly through the mother-child relationship. Conclusions These findings indicate an important role for quality of the mother-child relationship in determining outcomes for infants and young children of substance-using women, and emphasize the need to consider both the larger context of risk, as well as the mother-child relationship for best intervention outcomes.