The object of the study was to test the hypothesis that mental illness is associated with drug abuse by pregnant smokers. We abstracted data from the State of Missouri Risk Appraisal of Pregnant Women database on 239 (115 black and 124 white) women who attended an inner-city hospital from 1999 through 2000. Thirty-four percent abused drugs, 16% used alcohol, and 8% reported having a history of mental illness or psychiatric treatment. On multivariable logistic regression analyses, pregnant smokers were more likely to use drugs if they had mental illness (odds ration [OR], 7), consumed alcohol (OR, 2), or were black (OR, 3). In conclusion, drug abuse is associated with mental illness, suggesting that this behavior may be a marker of underlying mental illness among pregnant smokers. Therefore, in addition to initiating social service intervention, the identification of drug abuse by pregnant smokers should prompt a mental health evaluation.