Viloxazine was one of the first of the 'second-generation' antidepressants. Its relative lack of cardiotoxic, anticholinergic, sedative and seizure-inducing adverse effects suggested its use as an antidepressant in general hospitals where tricyclic antidepressants might be frequently contraindicated. We conducted a double-blind trial of 300 mg viloxazine against placebo in 43 patients with major depressive disorder. The placebo-treated group showed a slightly, but not significantly, greater improvement in depression scores using observer and self-rating scales over those using viloxazine. A review of previous placebo-controlled studies of viloxazine offers little support to its use as an antidepressant.