Despite the availability of several antidepressants, low patient compliance with medication, mainly due to adverse effects remains a major problem. The aim of this study was to evaluate the efficacy and compliance of tianeptine, a selective serotonin reuptake enhancer (SSRE), for the treatment of major depression in primary care setting of India. In a prospective observational multicentric study, 320 outpatients with major depression were treated with tianeptine 12.5 mg thrice daily for 60 days. Outcome measures were change in Hamilton depression rating scale (HDRS) score, frequency of side-effects, and compliance with medication. After treatment, mean HDRS score decreased from 10.9 +/- 3.2 at baseline to 6.9 +/- 2.7 at day 60 (p < 0.01), with more than half the patients showing > 50% improvement in HDRS score. No patient withdrew due to side-effects, which were reported in 23 patients (7.2%). Mean compliance with the medication was 91%. This study demonstrates the efficacy and acceptability of tianeptine in the management of major depression in Indian clinical practice.