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Both occupational conditions and individual factors have been shown as contributors to the likelihood of substance use among health professionals.To assess the use of Winick's (1974) model for explaining nurses' substance use, which asserts that groups with access to substances, freedom from negative proscriptions, and role strain have an increased likelihood of drug dependence.Data were analyzed from the 3,600 working nurses participating in the Nurses Worklife and Health Study, a nationally representative survey of registered nurses in the United States. A structural equation model was tested fitting workplace access to substances (availability, frequency of administration, and knowledge), freedom from negative proscriptions (internal: religiosity; external: social network), and role strain (job demands and depressive symptoms) to the frequency of past year alcohol, marijuana/cocaine, and prescription-type drug use.Nurses were more likely to use substances when workplace access to substances increased (p < 0.001), with social networks containing more drug users, and when religiosity decreased (p < 0.001). Role strain (measured through job demands and depressive symptoms) also was related to substance use. Depressive symptoms were related directly and negatively to substance use (p < 0.01), whereas job demands were related indirectly to substance use through depressive symptoms.Winick's model has use in explaining nurses' substance use. Research and preventive initiatives should consider the multidimensional aspects of substance use in nurses.