Atypical depression, with features of hypersomnia, hyperphagia, anergia, and rejection sensitivity, is a common presentation of major depressive disorder. There are few available effective therapies for this disorder. We test modafinil, a novel wake-promoting agent, as monotherapy for atypical depression in a double-blind, placebo-controlled, relapse prevention trial after open-label treatment. We found that modafinil significantly improved atypical depression symptoms during 12 weeks of open-label treatment (mean ± SD Hamilton Depression Scale (29-item version) score changed from 34 ± 8.2 at baseline to 9.7 ± 9.3, P < 0.0001), and that benefits were maintained alike in both the continuation and placebo arms during the double-blind treatment phase (P = 0.92). Modafinil was well tolerated and the drug was associated with significant weight loss compared with placebo (P = 0.01).