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Little research has focused on the association between self-concealment and health outcomes related to externalization, such as substance dependence. Integrating minority stress theory with recent findings rooted in ego depletion theory, the current study examined the association between self-concealment and drug dependence severity in a sample of young sexual minority men. Sexual minority men (N = 78) in New York City reporting substance use and sexual risk behavior completed an online survey in which they reported demographic, personality, and health information. Self-concealment was directly associated with both cognitive reappraisal (a proxy association for ego depletion) and with drug dependence severity. However, cognitive reappraisal did not account for an indirect association between self-concealment and dependence severity. Further, diminished cognitive reappraisal was associated with fewer symptoms of drug dependence. These results suggest that self-concealment is associated with drug dependence severity but that certain aspects of ego depletion may not account for the association in this sample. These results call for a multidimensional study of ego depletion and suggest the possibility of domain-differential effects of ego depletion on dependence severity within the context of self-concealment.