Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressant, yet it is not known whether one SSRI is more effective than another. To compare the effectiveness of 3 SSRIs (paroxetine, fluoxetine, and sertraline) in depressed primary care patients. Open-label, randomized, intention-to-treat trial, with patient enrollment occurring in April-November 1999. Thirty-seven clinics in 2 US primary care research networks. A total of 573 depressed adult patients for whom their primary care physician thought that antidepressant therapy was warranted and who completed a baseline interview. Patients were randomly assigned to receive paroxetine (n = 189), fluoxetine (n = 193), or sertraline (n = 191) for 9 months. Primary care physicians were allowed to switch patients to a different SSRI or non-SSRI antidepressant if they did not adequately respond to or tolerate the initial SSRI. The primary outcome measure was change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) Mental Component Summary score (range, 0-100), compared across treatment groups at 1, 3, 6, and 9 months. Secondary outcomes included other depression and psychological measures, multiple measures of social and work functioning, and other domains of health-related quality of life, such as physical functioning, concentration and memory, vitality, bodily pain, sleep, and sexual functioning. Follow-up interviews were successfully completed in 94% of patients at 1 month, 87% at 3 months, 84% at 6 months, and 79% at 9 months. Responses to the 3 SSRIs were comparable on all measures and at all time points. The mean change in the SF-36 Mental Component Summary score at 9 months was + 15.8 in the paroxetine group, + 15.1 in the fluoxetine group, and + 17.4 in the sertraline group. The drugs were also associated with similar incidences of adverse effects and discontinuation rates. The SSRI antidepressants paroxetine, fluoxetine, and sertraline were similar in effectiveness for depressive symptoms as well as multiple domains of health-related quality of life over the entire 9 months of this trial.