OBJECTIVES: Population based study to determine clinical consequences and economic impact of using escitalopram (ESC) vs. citalopram (CIT) and venlafaxine (VEN) in patients initiating treatment for a new episode of major depression (MD), in real-life conditions of outpatient practice. METHODS: Observational, multicenter, retrospective study conducted using computerized medical records (administrative databases) of patients treated in six primary care centers and two hospitals between January 2003 and March 2007. Study population: patients >20 years of age diagnosed with a new episode of MD who initiate treatment with ESC, CIT or VEN, and whithout any antidepressant treatment within the previous 6 months, who were followed for 18 months or more. Main variables: socio-demographic variables, remission, comorbidity, annual health care costs (medical visits, diagnostic and therapeutic tests, hospitalizations, emergency room and psychoactive drugs prescribed) and non-health care costs (productivity loss at work). Statistical analyses: logistic regression and ANCOVA models. RESULTS: A total of 965 patients (ESC=131; CIT=491; VEN=343) were included. ESC-treated patients were younger, with a higher proportion of males, and a lower specific comorbidity (p<0.01). ESC-treated patients achieved higher remission rates (58.0%) compared to CIT (38.3%) or VEN (32.4%) patients (p<0.001) and had lower productivity work  ESC (37.9 days) vs.CIT (32.7 days) or vs. VEN (43.8 days), p=0.042. No differences in average/unit costs of psychoactive drugs were observed between the ESC and CIT groups (€294.7 vs. €265.2), with higher costs seen in the VEN group (€643.0), p=0.003. In the corrected model, total (health care and non-health care) costs were lower with ESC (€2276.2) vs. CIT (€3093.8), p=0.047 and VEN (€3801.2), p=0.045. CONCLUSIONS: ESC appears to be dominant in the treatment of new MD episodes when compared to CIT and VEN, resulting in higher remission rates and lower total costs.