The present meta-analysis addressed the empirical evidence regarding the treatment of major depression with atypical features. The superiority of monoamine oxidase inhibitors (MAOIs) compared with other antidepressants in the treatment of major depression with atypical features has been frequently reported. According to the CONSORT Statement, studies included in our meta-analysis had to meet several criteria, especially a double-blind, controlled condition and an operational diagnosis according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-III or DSM-IV criteria, respectively. Four databases for research-based evidence were used in a systematic review: Medline, Embase, Psyndex and PsycInfo. Only eight publications met inclusion/exclusion criteria, resulting in 11 comparisons. Our results contrast an effect size of 0.45 (95% confidence interval) for a comparison of MAOIs vs. placebo with an effect size of 0.02 (95% confidence interval: - 0.10-0.14) for a comparison of MAOIs vs. selective serotonin reuptake inhibitors. The effect size for MAOIs vs. tricyclic antidepressants was 0.27 (95% confidence interval: 0.16-0.42). MAOIs may be more effective for atypical major depressive disorder than tricyclic antidepressants. Most clinical research has been conducted on irreversible MAOIs. Additional studies testing more recently developed antidepressants (including reversible MAOIs) with an improved safety profile would be warranted. The available data are insufficient for a direct comparison between MAOIs and selective serotonin reuptake inhibitors.