To examine the antidepressant specificity of fluoxetine in Huntington's disease (HD), we carried out a randomized, double-blind, placebo-controlled trial of this medication in nondepressed HD patients. Thirty patients with early HD who were depressed (Hamilton Depression Inventory < 16) were randomized to placebo (N = 13) or fluoxetine 20 mg/day (N = 17) and were followed up for 4 months. Outcome measures included changes in total functional capacity (TFC) and in standardized neurological, cognitive, and behavioral ratings. After adjustment for the higher education level found in the placebo group at baseline, no differences between the treatment groups were found in TFC, neurological, or cognitive ratings. Fluoxetine-treated patients did show a slight reduction in agitation and in the need for routine. Although fluoxetine may be a useful antidepressant in depressed HD patients, it failed to exert substantial clinical benefits in nondepressed HD patients.