INTRODUCTION: Sertraline and fluoxetine have different pharmacologic and pharmacokinetic profiles, which may be of clinical relevance in the determination of treatment response in different subtypes of depression. OBJECTIVES To analyse the efficacy of sertraline and fluoxetine in a subgroup of 78 patients with evidence of significant psychomotor agitation (HAM-D item 8 less than or equal to 1 and HAM-D item 9 greater than or equal to 2 at study entry) in a 6-week study comparing sertraline (50-100 mg/day) and fluoxetine (20-40 mg/ day) for the treatment of major depression in 286 psychiatric outpatients. RESULTS: The proportion of patients with psychomotor agitation responding (greater than or equal to 50% reduction HAM-D score) at last visit was significantly (P < 0.05) higher in the sertraline group than in the fluoxetine group (62% vs 39%, respectively). Most of the secondary efficacy parameters showed significantly (P < 0.05) greater improvement in the sertraline treatment group at last visit: HAM-D less than or equal to 8, HAM-D total score, HAM-D anxiety/ somatization factor, HAM-D weight factor, HAM-A total score, CGI-S, Raskin Depression score, and Covi Anxiety score. CONCLUSION: The findings of this retrospective data analysis suggest that fluoxetine may be a less efficacious antidepressant than sertraline in patients with psychomotor agitation.