Gender differences in risk and protective factors for substance use/abuse in early adulthood were studied. Comprehensive systematic data on African-American males (N = 318) and females (N = 322), from birth to 7 years of age, were available from the National Collaborative Perinatal Study. These subjects were retrieved for assessment at average age 24. There are more differences between males and females than there are similarities in regard to the early childhood variables that predict substance use in early adulthood. However, high activity and intensity of response during infancy (measured at 8 months of age) was found to predict later substance use for both males and females. This type of behavior is considered by use to be a trait of temperament and to suggest the possibility of a genetic predisposition. More risk factors were found for female than for males. The risk factors for females were primarily of two types: 1) Related to experiences with mother and with the family environment; and 2) Poor levels of intellectual functioning and academic performance, and abnormal mental status.