This paper explores the parenting of drug-dependent women and the contributions of comorbid psychopathology to their parenting. A sample of 32 children whose mothers were dependent on opioid drugs during pregnancy and 37 children whose mothers were not drug users were followed from birth to middle childhood. Multivariate regression analyses were conducted contrasting whether maternal substance abuse or psychopathology was more closely linked to parenting behaviors and continuity in parenting over time. Maternal drug dependence was related to whether mothers were able to remain primary caregivers for their children over time, even after controlling for psychopathology. Maternal drug use was related to unresponsive and negative parenting behavior during mother–infant interaction, but this relation was largely accounted for by the effects of comorbid maternal psychopathology on parenting, particularly symptoms of antisocial and related personality disorders. For those children whose mothers continued to care for them into middle childhood, perceptions of their mothers as rejecting were related to maternal antisocial personality and maternal depression. Substance-abuse treatment for women should be integrated with interventions addressing their mental health and parenting needs.