This study examines prostitution, homelessness, delinquency and crime, and school problems as potential mediators of the relationship between childhood abuse and neglect (CAN) and illicit drug use in middle adulthood. Children with documented cases of physical and sexual abuse and neglect (ages 0-11) during 1967-1971 were matched with non-maltreated children and followed into middle adulthood (approximate age 39). Mediators were assessed in young adulthood (approximate age 29) through in-person interviews between 1989 and 1995 and official arrest records through 1994 (N = 1,196). Drug use was assessed via self-reports of past year use of marijuana, psychedelics, cocaine, and/or heroin during 2000-2002 (N = 896). Latent variable structural equation modeling (SEM) was used to test: (1) a four-factor model with separate pathways from CAN to illicit drug use through each of the mediating risk factors and (2) a second-order model with a single mediating risk factor comprised of prostitution, homelessness, delinquency and crime, and poor school performance. Analyses were performed separately for women and men, controlling for race/ethnicity and early drug use. In the four-factor model for both men and women, CAN was significantly related to each of the mediators, but no paths from the mediators to drug use were significant. For women, the second-order risk factor mediated the relationship between CAN and illicit drug use in middle adulthood. For men, neither child abuse and neglect nor the second-order risk factor predicted drug use in middle adulthood. These results suggest that for women, the path from CAN to middle adulthood drug use is part of a general "problem behavior syndrome" evident earlier in life.