Medifoxamine (Clédial TM), a non tricyclic non MAOI antidepressant drug with a dopaminergic and serotoninergic mechanism of action, was compared to imipramine in a multicenter double blind trial. Patients suffering from DSM III-R major depression (without psychotic features), with a minimum inclusion score of 25 at the MADRS after an initial 7-day wash-out period, were randomly assigned to a 4-week treatment by either imipramine or medifoxamine, with flexible doses of at least 100 mg after 2 weeks of treatment. No associated treatment was permitted except for lorazepam 2 to 5 mg per day. Ninety eight patients were recruited by 20 centers throughout France. Eighty four terminated the 4-week protocol. Early terminations were due to serious adverse events (3), death on imipramine (1), protocol violation (1), refusal to continue (1), loss to follow up (1). The 2 groups of patients were comparable on inclusion. In the medifoxamine group (receiving a daily dose of 194 mg at day 28) the percentage of improvement in MADRS scores, the number of patients with a MADRS improvement of a least 50% and a final MADRS score inferior to 8, were not significantly different from the imipramine group (daily dose: 161 mg at day 28). No more difference appeared when several clinical variables were analyzed, in particular the DSM III-R melancholic, the Newcastle endogenous subtypes and the in or out patient status. The two treatment groups were also comparable on other scales (HDRS, HARS assessing anxiety, CGI).(ABSTRACT TRUNCATED AT 250 WORDS)