Objectives: To determine whether social support and depressive symptoms mediate the relationship between poverty and substance use in tuberculosis (TB) patients in South Africa. Methods: We performed structural equation modeling with the latent constructs socioeconomic status (SES), social support and "substance use" (tobacco smoking, alcohol problem, illicit drug use) in 1005 male TB patients. Results: Higher SES directly (standardized coefficient= -0.27) and indirectly reduced substance use. Indirectly SES provided increased social support (coefficient=0.37), which was associated with reduced substance use (coefficient=-0.15). Higher SES diminished depressive symptoms. Model fit was acceptable. Separate models for tobacco smoking, illicit drug use or alcohol problem produced similar findings. Conclusions: Poverty alleviation and social support-based interventions may benefit male TB patients with substance use.