Outpatients aged 18-65 who met Feighner et al. criteria for primary affective disorder-depression and had Hamilton Depression Rating Scale (HDRS) scores greater than or equal to 20 were randomly assigned to receive nomifensine (N = 61) or placebo (N = 63) for 4 weeks. On all measures of efficacy (HDRS, Clinical Global Impressions, Hopkins Symptom Check List, Brief Psychiatric Rating Scale), patients treated with nomifensine showed significant improvement compared to placebo patients; improvement was evident after 1 week on some scales. No clinically important changes were seen over the course of treatment in findings of physical examinations, ECGs, and clinical laboratory evaluations. Side effects associated with active treatment were mild to moderate in severity and rarely led to cessation of therapy. Thus, significant clinical improvement was seen in these moderately to severely depressed outpatients, without significant adverse experiences.