Context: Federally qualified health centers across the country are adopting depression disease management programs following federally mandated training; however, little is known about the relative effectiveness of depression disease management in rural versus urban patient populations. Purpose: To explore whether a depression disease management program has a comparable impact on clinical outcomes. Over two years patients treated in rural and urban primary care practices and whether the impact is mediated by receiving evidence-based care (antidepressant medication and specialty care counseling). Methods: A preplanned secondary analysis was conducted in a consecutively sampled cohort of 479 depressed primary care patients recruited from 12 practices in 10 states across the country participating in the Quality Enhancement for Strategic Teaming study. Findings: Depression disease management improved the mental health status of urban patients over 18 months but not rural patients. Effects were not mediated by antidepressant medication or specialty care counseling in urban or rural patients. Conclusions: Depression disease management appears to improve clinical outcomes in urban but not rural patients. Because these programs compete for scarce resources, health care organizations interested in delivering depression disease management to rural populations need to advocate for programs whose clinical effectiveness has been demonstrated for rural residents.