The authors examined the efficacy of ketoconazole in 16 adults with treatment-refractory major depressive disorder. Subjects participated in a 6-week, double-blind, placebo-controlled trial. Assessments of mood were made using the Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory (BDI), and the Clinical Global Impression Scale (CGI). Results showed that none of eight patients randomly assigned to receive placebo and two of eight patients randomly assigned to receive ketoconazole met criteria for response. As a group, patients assigned to receive ketoconazole showed no significant reductions in HAM-D, BDI, or CGI scores during the 6-week trial compared with those receiving placebo. These findings suggest a limited efficacy for ketoconazole in patients with treatment-refractory major depression.