IMPORTANCE: In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor. OBJECTIVE: To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer. INTERVENTIONS: Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome measurewas the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment. RESULTS: Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects. CONCLUSIONS AND RELEVANCE: Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia. © 2013 American Medical Association. All rights reserved.