Patients with the HIV infection are at high risk for developing depression. The aim of this study was to investigate the safety and efficacy of antidepressant effects of minocycline on HIV patients with depression. Forty-six HIV patients, with mild-to-moderate depression and a Hamilton Depression Rating Scale (HDRS) up to 18, participated in a parallel, randomized, double-blind, placebo-controlled trial and underwent 6 weeks of treatment with either minocycline (100 mg twice daily) or placebo in the same manner. Patients were assessed using HDRS at baseline and at weeks 3 and 6. The primary outcome measure was to evaluate the efficacy of minocycline in improving depressive symptoms. General linear model repeated measures showed significant effect for time × treatment interaction on the HDRS score during the trial course [F(2, 88)=7.50, P=0.001]. There was no significant difference between the two groups regarding adverse events. No serious adverse event was reported. The administration of 100 mg minocycline twice daily seems to be safe and effective in improving depressive symptoms in HIV/AIDS patients with mild-to-moderate depression.