BACKGROUND: Chromium picolinate (CP) has been reported to benefit patients with symptoms of atypical depression. METHODS: A placebo-controlled, double-blind, pilot study of CP was conducted in 15 patients with DSM-IV major depressive disorder, atypical type. Patients received 600 micro g of CP or matching placebo (PBO) for 8 weeks. RESULTS: Seven (70%) CP and zero (0%) PBO patients met responder criteria (p =.02). Other outcomes were consistent with greater effect of CP. Three patients on CP failed to show any improvement. Chromium picolinate was well tolerated. CONCLUSIONS: Chromium picolinate shows promising antidepressant effects in atypical depression. Its mechanism of action may relate to 5HT2A downregulation, increased insulin sensitivity, or to other effects.