This study examines the relationship of substance use to birth outcome, infant, and maternal health in a large, nationally representative sample. Multiple regression analyses, accommodating the nature of the survey data using the SUDAAN software package, indicated that drinking and smoking independently and/or interactively with depression account for poor health and serious medical conditions among pregnant women as well as negative birth outcomes or adverse health consequences in those infants who are live births. In addition, African American women and their infants are more likely than those of other racial groups to suffer these adverse outcomes. Given the risk profiles of individual illnesses, this study suggests the need for developing and targeting health education and preventive efforts specific to those groups that are clearly at greater risk.