Quality of life (QOL) in depression could be of great value as an outcome measure, especially in determining the effectiveness of treatment strategies. However, for this aim to be accomplished, it is important to clarify the relationship between QOL and a number of potentially mediating factors, such as sociodemographic and clinical variables. For this purpose, we assessed 140 depressed outpatients with the Mini International Neuropsychiatric Interview, the WHOQOL BREF, and the Beck Depression Inventory (BDI). After standard and stepwise multiple regression analyses, the following variables were found to be independent predictors of QOL: BDI score for the physical (adjusted R(2)=0.125) and psychological (adjusted R(2)=0.23) domains, and for the overall QOL estimate (adjusted R(2)=0.226); age, suicidality according to the MINI and BDI score for the social relations domain (adjusted R(2)=0.244); and ethnicity, psychiatric comorbidity, psychotic symptoms and BDI score for the environmental domain (adjusted R(2)=0.328). Limitations of the study include its cross-sectional design, relatively small sample size, and lack of objective measures of depressive symptomatology. Sociodemographic and clinical variables appear to explain less than 32.8% of the variance of QOL in subjects with depressive disorders. Clearly, further studies are needed to clarify which additional factors play a role in determining QOL in major depression.