The aim of this study is to compare the efficacy and safety of clomipramine and sertraline in patients with premature ejaculation. The study included total 33 patients, with true premature ejaculation (PE), age ranged from 23 to 45 years old (mean: 30.5 years). The patients were randomly divided into 3 groups; 12 patients as ciomipramine group, 11 patients as sertraiine group and 10 patients as placebo group. Each patient took 1 capsule daily for the first week, then 2 daily for trie remaining 7 weeks. The efficacy of each drug was assessed With intravaginal ejaculation latency time and sexual satisfaction rate of patient and partner, and side effects of drugs were recorded. Mean intravaginal ejaculation time increased from 1.45 minutes (0.5-2 minutes) to 5.5±2 minutes, 5±2 minutes and 2.5±1.5 minutes in clomipramine, sertraline and placebo-groups respectively. Sexual satisfaction rates of patients and partners were parallel with that intravaginal ejaculation durations. Side effect ratios were 90 % in clomipramine group and 60 % in sertraline group. Although the incidence of side effects with clomipramine was significantly higher compared to that of sertraline (p<0.01), no significant difference was obtained between clomipramine and sertraline in terms of efficacy (p>0.5). As a result sertraline is as effective as clomipramine in treatment of PE with minimal side effects compared to those of clomipramine. Thus, we recommend that sertraline should be the first choice in the treatment of PE.