Objective To evaluate the clinical effectiveness and safety of escitalopram in the treatment of major depression. Methods A randomized double-blind active-drug controlled trial was used to observe 56 patients with major depression. They were randomly divided into the treatment group (escitalopram, 28 patients) and the control group (citalopram, 28 patients). We used HAMD,CGI-I, and HAMA to evaluate clinical effectiveness and symptom-recording to evaluate safety. All outcomes were measured before treatment and at 14 days, 28 days and 42 days after treatment. Results According to an intention-to-treat (ITT) analysis in the Full Analysis Set with last observation carried forward (LOCF), the HAMD score decreased from baseline by 15.1±7.8 in the treatment group, and 12.1±7.7 in the control group. There was no significant difference between the two groups(t=1.42,P=0.1613). The rate of effectiveness, based on the percentage decrease of HAMD is 78.6% in the treatment group, and 67.9% in the control group(χ2 = 0.8195,P=0.3653). The HAMA score decreased from 15.1±3.7 to 3.3±4.5 in the treatment group, and from 14.0±4.1 to 5.0±3.7 in the control group(t=1.5756, P=0.1223). From the point of CGI, there was no significant difference between these two groups at any follow-up. At the end of the trial, the proportion of patients assessed to have a great improvement or more was 90.0% in the treatment group, and 87.8% in the control group (CMH=1.5013,P=0.2205). Side effects were recorded for 32.5% of the treatment group and 30.8% of the control group(χ2 =0.0770, P=0.7814). The most frequent side effects were nausea(11.7%), dry mouth(9.2%), dizziness(5.8%), insomnia(3.3%), hypodynamia(2.5%), transaminase elevation(1.7%), palpitation(1.7%), and constipation(1.7%). Conclusion The therapeutic action of escitalopram for the treatment of major depression is confirmed with less side effects than the well-proven antidepressant- citalopram.