Objective: The limitations of antipsychotic therapy in schizophrenia and schizoaffective disorder led to the investigation of the putative utility of pharmacologic augmentation strategies. The antitumor agent bexarotene via nuclear retinoid X receptor (RXR) activation might modulate numerous metabolic pathways involved in the pathogenesis of schizophrenia and schizoaffective disorder. This trial aimed to investigate efficacy and safety of add-on bexarotene to ongoing antipsychotic treatment of patients with schizophrenia or schizoaffective disorder. Method: Ninety inpatients and outpatients that met DSM-IV-TR criteria for schizophrenia or schizoaffective disorder participated in a 6-week, double-blind, randomized, placebocontrolled multicenter study. Bexarotene (75 mg/d) was added to ongoing antipsychotic treatment from October 2008 to December 2010. The reduction in the severity of symptoms on the Positive and Negative Syndrome Scale (PANSS) was a primary outcome. Secondary outcomes ncluded general functioning, quality of life, and side effect scales. Results: Seventy-nine participants (88%) completed the protocol. Controlling for antipsychotic agents, a mixed model showed that patients who received adjunctive bexarotene had significantly lower PANSS positive scale scores compared to patients who received placebo (F = 8.6, P = .003; treatment arms × time, F = 2.7, P = .049), with moderate effect size (d = 0.48; 95% CI,0.04-0.93). Patients with mean or higher baseline PANSS positive scale scores and patients who did not take lipid-reducing agents revealed greater amelioration of positive symptoms (F = 7.4, P = .008). Other symptoms and secondary outcome measures were not affected by adjunctive bexarotene. Bexarotene was well tolerated, though 2 reversible side effects were reported: a significant increase in total cholesterol levels (P < .001) and a decrease in total thyroxine levels (P < .001). Conclusions: Bexarotene might potentially be a novel adjuvant therapeutic strategy for schizophrenia, particularly for the reduction of positive symptoms. The potential benefits and risks of ongoing administration of bexarotene warrant further evaluation.