Objective: Depressive disorders pose a major challenge to healthcare in the countries of the former Soviet Union. The objective of the current study was to evaluate health-related quality of life (HrQoL) and its determinants in outpatients with major depressive disorder in an urban Russian population. Methods: We consecutively recruited 100 urban Russian outpatients with major depression and 100 non-depressed controls who were matched for age and sex. The severity of their depression was assessed using the Hamilton Depression Rating Scale (HDRS). HrQoL was evaluated using the EuroQol (the EQ-5D and the visual analogue scale, EQ VAS). Independent determinants of HrQoL were identified using multiple regression analysis. Results: The mean EQ VAS score was 43.0 + 27.4 in patients with depression compared to 81.4 + 14.7 in the controls ( p < 0.01). Out of the domains of the EQ-5D, “anxiety/depression,” “usual activities,” and “self-care” were the most impaired. Independent determinants of reduced HrQoL were: severity of depression according to the HDRS; violent suicide attempts; suicide attempts in the past; and drug addiction. Conclusions: HrQoL is considerably reduced in Russians with major depression. The disease-specific patterns of HrQoL impairment and the independent determinants of HrQoL identified in our study could be addressed in focused healthcare programs and clinical trials. Comorbid drug addiction as a determinant of HrQoL should receive greater attention in the management of depressive disorders in urban Russian populations.