Depression that fails to respond to multiple antidepressant trials, particularly when accompanied by anxiety, constitutes a difficult treatment challenge. Those with anxious depression may be less likely to respond to treatment than their cohorts without anxiety. Anxiety symptoms also predict a higher rate of suicide, particularly if the symptoms do not improve early in the course of treatment. Eleven consenting outpatients with treatment-resistant depression and/or comorbid anxiety disorders were treated with nefazodone, slowly added to their ongoing treatment regimens. Doses were initiated at 50 mg a day and slowly increased by 50 mg increments until an optimum response was achieved. The Clinical Global Impression of Improvement (CGI) Scale was employed to monitor the medication effects. In all 11 cases, nefazodone was efficacious and well tolerated in the treatment of both depressive and anxiety components. After nefazodone augmentation, the mean CGI score for combined depression and anxiety symptoms was (7sd) 1.52 (0.52) on a scale from 1 (very much better) to 7 (very much worse). Seven of the 11 cases achieved complete remission of depressive symptoms (v 2 ΒΌ11.55, Po.005) and 9 of the 11 cases, complete remission of anxiety symptoms (v 2 ΒΌ15.23, Po.0005). The mean effective dose for nefazodone (mean7sd) was 200.0 (34.2) mg a day (range 50-300 mg a day). Nefazodone's unique pharmacologic profile may explain its unusual efficacy in these cases of treatment-resistant major depression.