The selective noradrenaline re-uptake inhibitor reboxetine may have advantages over the selective serotonin re-uptake inhibitors fluoxetine and citalopram, in effects on sexual function and satisfaction. The effects of reboxetine and paroxetine on sexual function were compared by examining data from the UK centres in an international double-blind flexible-dose parallel-group multi-centre randomized controlled trial of acute treatment of patients with DSM-IV major depression. Patients were randomly assigned to receive reboxetine (4 mg b.d.) or paroxetine (20 mg mane) using a double-dummy technique to preserve the blind. The dosage could be increased at day 28 (to reboxetine 4 mg mane, 6 mg nocte; or paroxetine 20 mg b.d.). Antidepressant efficacy was assessed by the 21-item Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impression Scale for Severity (CGI-S) at all study visits, and the Clinical Global Impression of Improvement (CGI-I) at each visit after randomization. Sexual function and satisfaction was assessed by visual analogue scale (VAS) items of the Rush Sexual Inventory completed at baseline and days 28 and 56. There were no significant differences between groups in demographic or clinical features at baseline. There was a gradual reduction in severity of depressive symptoms (reboxetine, 14.3; paroxetine, 12.0: observed case analysis), with no significant differences between groups. There were significant differences (p 0.05), with advantages for reboxetine, at Week 4 and Week 8 on the VAS item assessing ability to become sexually excited, and non-significant trends with advantages for reboxetine, in frequency of sexual thoughts at Week 4 (p 0.05) and Week 8 (p 0.08); and in desire to initiate sexual activity at Week 4 (p 0.09). Exclusion of patients who had ever experienced sexual dysfunction with any medication prior to participation in this study (n 10) reduced the statistical significance of the findings, although there were still numerical advantages for reboxetine. Sexual function and satisfaction in depressed patients improves during double-blind acute treatment with reboxetine or paroxetine, but this improvement is greater and more rapid with reboxetine.