BACKGROUND: We examined the association between substance use (SU) disorder and mortality among HIV-infected patients in a large, private medical care program. METHODS: In a retrospective cohort design, HIV-infected patients (>/=14 years old) from a large health plan (Northern California) were studied to examine mortality associated with diagnosis of SU dependence or abuse over an 11-year period. RESULTS: At study entry or during follow-up, 2,279 (25%) of 9,178 HIV-infected patients had received a diagnosis of SU disorder. Diagnoses were categorized as alcohol dependence/abuse only, illicit drugs only, or both. Cause of death differed by the category of SU diagnosis. Mortality rates ranged from 35.5 deaths per 1,000 person-years in patients with an SU disorder to 17.5 deaths among patients without an SU disorder. Regression results indicated mortality risk was significantly higher in all categories of SU disorder compared to no SU diagnosis (hazard ratios ranging from 1.65 to 1.67) after adjustment for SU treatment and confounders. CONCLUSIONS: A diagnosis of SU dependence/abuse is associated with higher mortality among HIV-infected patients for whom access to medical services is not a significant factor.