The relative and combined health effects of cigarette smoking, heroin use, and depression were examined in 322 clinically depressed smokers and 117 opioid-dependent smokers participating in two studies of the San Francisco Treatment Research Center. Opioid-dependent smokers averaged 16 years (S.D.=9) of heroin use; 3% of depressed smokers used opiates in the past 6 months. Cigarettes per day (M=15, S.D.=10) and Beck Depression (BDI-II) scores (M=21, S.D.=11) were comparable between the two groups. Health functioning was assessed using the Medical Outcomes Study Short Form (SF-36). Adjusting for demographic differences, depressed smokers reported better physical but poorer emotional health relative to opioid-dependent smokers. Both groups scored significantly lower than published norms (p<.05). Within groups, severity of depressive symptoms, tobacco use, and opiate use were independent predictors of lower health functioning (p<.05). Examining risk-related subgroups based on depression scores (BDI-II> or =20), cigarettes per day (> or =1 pack), and opiate use, number of risk factors was monotonically related to health functioning in both samples. Individuals with two or more risk factors scored the lowest (p<.05). Severity of depressive symptoms, tobacco use, and opiate use contributed individually and collectively to lower health functioning. Blended treatments that target multiple risk factors are needed to improve health outcomes.