Background: It is difficult to improve negative symptoms and cognitive impairments in schizophrenia. A previous pilot study has shown that minocycline, a semi-synthetic second-generation tetracycline, is effective in treating for negative and/or cognitive symptoms in schizophrenia. Objectives: The present study was designed to examine the efficacy and safety of minocycline for the treatment of negative symptoms and cognitive impairments in patients with schizophrenia. Methods: Ninety-two patients with early stage schizophrenia treated with risperidone entered this 16-week, double blind, randomized, placebo-controlled clinical trial. Subjects were randomly assigned to receive minocycline (200 mg per day) or the placebo. The primary outcome was evaluated using the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the response rate of SANS, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI), and cognitive tests. Results: Subjects receiving minocycline had greater improvements on SANS total scores and PANSS negative subscale scores (P < 0.001) when compared with those receiving the placebo. Rates of treatment response (43.6%) in the minocycline group were significantly higher than those in the placebo group (10.0%) after 16 weeks of treatment. There was no significant difference between the seven cognitive domains (P > 0.05), except for the attention domain (P = 0.044). Conclusions: The addition of minocycline to atypical antipsychotic drugs in early schizophrenia had significant efficacy on negative symptoms but had a slight effect on the attention domains of patients with schizophrenia. It may be considered as a new adjunct treatment for negative symptoms of schizophrenia. Clinical trials.gov identifier: NCT01493622. (C) 2014 Elsevier B. V. All rights reserved.