AbstractSixteen patients meeting our criteria for atypical depression were treated in a 7‐week single‐blind pilot study with cilobamine mesylate, an investigational antidepressant structurally distinct from tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI). Nine patients (56 per cent) responded to cilobamine. Cilobamine patients were compared with a group of similar patients receiving placebo for 6 weeks in a separate double‐blind study. The response rate to cilobamine was superior to that of placebo. Cilobamine patients also showed significantly greater improvement in Hamilton Depression Scale scores than did placebo patients. Previous studies have demonstrated the efficacy of MAOIs in atypical depression. This study suggests that certain antidepressants which are not MAOIs, and are free of dietary restrictions and the risk of hypertensive crises, may also be effective in atypical depre