Fluoxetine and trazodone were compared in a double-blind, randomized, parallel, 6-week trial in 43 outpatients with major depression after a 1-week single-blind placebo period. Thirty-five patients completed at least 3 weeks of active medication, while 25 patients completed all 6 weeks. Response rates, whether defined by end-of-treatment Hamilton Rating Scale for Depression (HAM-D) score less than 10 or by a 50% reduction in HAM-D scores, were equivalent for the two medications. For fluoxetine, HAM-D scores were significantly lower at Weeks 1 and 2 compared with those of trazodone. Trazodone improved sleep significantly more than fluoxetine. Fluoxetine was associated more frequently with weight loss (p = .002) and less frequently with dizziness (p = .04) than trazodone.