Objective: Guidelines recommend use of antidepressants for a minimum of six months in major depressive disorder in order to decrease the risk of relapse. Persistence on treatment depends both on efficacy and tolerability. In clinical trials, escitalopram has shown a better efficacy and equivalent tolerability compared with citalopram. This work compares persistence on treatment at six months and associated economic consequences, for treatment with escitalopram vs. citalopram. Methods: Using US denominator-based claims database PharMetrics (includes data from 86 managed care health plans covering 45 million patients), we included adult patients diagnosed with depression who started escitalopram or citalopram between January 1, 2003 and December 31, 2004. Six-months persistence was defined as the percentage of patients still on treatment at 6 months. We compared persistence over time using Cox model, and health care costs at 6 months using log-linear regression. Propensity scoring was used to account for channelling by indication. Results: A total of 13,227 patients started escitalopram; 3,624 patients started citalopram. Persistence at 6 months was 20.4% with escitalopram vs. 16.2% with citalopram (p<0.001). Escitalopram-treated patients were more likely to be persistent over 6-months than citalopram-treated patients adjusted for their baseline characteristics (HR=0.896; 95%CI=[0.859-0.934]). More were observed on citalopram than on escitalopram (7.8 vs. 6.2; p<0.001). Total healthcare costs over 6-months (including treatment cost) were non-significantly lower for escitalopram-treated patients than for citalopram-treated patients (-USD232 per patient; p=0.2). Persisters at 6 months incurred less total health care costs than non-persisters (-USD280 over the 6 months). Conclusion: Persistence at 6 months is higher on escitalopram than on citalopram, in consistency with its better efficacy profile. Persistence at 6 months is recommended to maximise chances of sustained remission and to avoid relapse; interestingly these results show that persistence is also associated with decreased health care costs. Efforts should be made to promote persistence on antidepressant treatment.