Paroxetine is a novel phenylpiperidine antidepressant agent that acts as a potent and selective inhibitor of serotonin reuptake. We report results of a 6-week, randomized, double-blind, multicenter study comparing paroxetine and fluoxetine in the treatment of major depression. One hundred seventy-eight inpatients, who met DSM-III-R criteria for a major depressive episode and had a Montgomery Asberg Depression Rating Scale (MADRS) score of 24 or more, were included in the study. Their ages ranged from 18 to 65 years. Subjects were randomized to receive either paroxetine or fluoxetine for 6 weeks. A 20-mg fixed dose, given once daily in the morning, was used for both drugs. After baseline, regular assessments were made at the end of weeks 1, 2, 3, 4, and 6. Efficacy measures included the MADRS, the Clinical Global Impression severity of illness scale, the Hamilton Rating Scale for Anxiety, the Hospital Anxiety and Depression scale, and the Visual Analogue Scale for anxiety. Safety and tolerability were assessed by adverse event reports, clinical examinations, vital signs, and laboratory data. A marked antidepressant response and good tolerability were seen with both drugs. These results further support the usefulness of paroxetine in the treatment of depressive illness.