To determine the effects of prenatal cocaine use on the medical and neurodevelopmental outcomes of infants from a rural, public health population, we interviewed over 2,000 women prenatally, identified 154 cocaine users and matched 154 controls on location/level of prenatal care, race, parity, and SES. Drug screening was done at the first prenatal visit and at delivery; detailed psychosocial/drug histories were taken at each trimester and follow-up visit. The cocaine group had significantly less prenatal care (92% vs. 97%), begun later (15 vs. 12 weeks), and were more likely to drink (76% vs. 31%), smoke (79% vs. 24%) and use marijuana (43% vs. 7%). There was no other illicit drug use in either group and marijuana was not related to any birth outcomes. There were no differences in fetal/perinatal deaths between groups but more preterms among cocaine users (17% vs. 9%). Ponderal Index did not differ between cocaine users and controls, but after controlling for alcohol and tobacco use, there remained a significant decrease in birthweight due to prenatal cocaine use. Head and chest circumference and length were significantly lower in cocaine users who also smoked tobacco. The average cocaine use per day for trimesters 1, 3 and overall pregnancy was significantly negatively related to birth length; and amount used in trimesters 2 and 3 was negatively related to head circumference. There were no significant group differences on any Brazelton cluster scores (by blinded certified examiners), but amount of alcohol used in the 2nd trimester was significantly negatively related to Brazelton motor scores. There were also dose-response effects of prenatal alcohol and tobacco use on birthweight, length, head and chest circumference. Because of the complexity of effects of cocaine exposure on birth outcome, evaluation of growth and development of infants should also consider the interactive effects as well as the amount and timing of drug exposure.