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To compare the efficacy of sustained-release (SR) bupropion to placebo in treating hypoactive sexual desire disorder (HSDD) in ovulating women.After a 1-week, placebo lead-in phase, 232 treatment-seeking women with regular menstrual cycles were randomly assigned to bupropion SR 150 mg/daily (116) or placebo (116) for 12 weeks under double-blind conditions. Efficacy was assessed with the Brief Index of Sexual Functioning for Women (BISF-W), the Personal Distress Scale (PDS), the global efficacy question (GEQ; ‘Did the treatment you received during the 12-week improve meaningful your sexual desire?’) and overall patient satisfaction question (‘Are you satisfied with the efficacy of your treatment?’).The mean (SD) composite score on the BISF-W, increased from 15.8 (2.6) and 15.5 (2.2) at baseline to 33.9 (4.2) and 16.9 (2.6) in the bupropion and placebo groups, respectively (P = 0.001). The odds ratio (95% confidence interval) for response in the bupropion group relative to placebo was 3.2 (2.1–6.3). The thoughts/desire score more than doubled in patients treated with bupropion (P = 0.001). At the 12-week evaluation the reduction in the PDS scale was 29.4% in bupropion and 4.7% in the placebo group (P = 0.01). In response to the GEQ, of patients in the bupropion and placebo groups, 65.3%, and 4.3%, respectively, responded ‘Definitely yes’ (P = 0.001). Of patients in the bupropion and placebo groups, 71.8%, and 3.7%, respectively, were definitely satisfied with the efficacy of their treatment, (P = 0.001). After 12 weeks of treatment, 82 women (78.1%) in the bupropion and five (4.9%) in the placebo group were willing to continue therapy (P = 0.001).The results from this study indicate that bupropion SR is an effective and well-tolerated treatment for HSDD in ovulating women. Further controlled trials are warranted.