The purpose of this research was to estimate the prevalence of substance abuse and depression among a population-based sample of registered nurses. In addition, to estimate the degree to which substance abuse and depression were associated with nurses, a comparison was made between nurses and other employed individuals. Respondents were obtained from a probability sample of households that were part of the National Institute of Mental Health Epidemiologic Catchment Area Program (ECA). Of the adults interviewed as part of the ECA, 143 were under age 65 and currently working as registered nurses. These nurses were matched by neighborhood of residence (census tract) and gender to a comparison group of non-nurses from the ECA who were also employed at the time of interview. Estimates of the odds of substance use and depression among the nurses (n = 143) and non-nurses (n = 1410) were calculated. Nurses were no more likely to have engaged in illicit drug use or to have experienced depression than non-nurses. Nurses were also less likely to have experienced problems with alcohol abuse than non-nurses.