We examined the effectiveness of reboxetine, a norepinephrine reuptake inhibitor (NRI), compared with placebo for the treatment of patients with severe major depression (defined as a score on the 17-item Hamilton Rating Scale for Depression [HAM-D] >/=25). Data were obtained from four prospective, double-blind, randomized, placebo-controlled clinical trials of the efficacy of reboxetine (8 to 10 mg/d) over 4 to 8 weeks in patients with major depression. In three of the trials, reboxetine produced a significantly greater reduction than placebo in mean HAM-D scores from baseline to the last clinical assessment (p < 0.001). There were significantly more responders to treatment (defined as a reduction in HAM-D score >50% between baseline and the last follow-up observation) treated with reboxetine than placebo in three trials. The overall mean responder rate with reboxetine was 63% (range: 56-74%) compared with 36% (range: 20-52%) with placebo. These results demonstrate that reboxetine is significantly more effective than placebo in a subgroup of patients with severe depression.