This large randomized controlled trial examined the effect of naproxen, simvastatin or both on patients with schizophrenia. This was a large multi-center, twelve-week, randomized, double-blind, placebo-controlled, four-arm clinical trial administering naproxen, simvastatin or both to 232 subjects with schizophrenia or schizoaffective disorder. The primary outcome was change in PANSS total score. ANCOVA and mixed model analyses of the PANSS total score change showed no significant difference between naproxen and placebo (adjusted p = 0.78), simvastatin and placebo (adjusted p = 0.38) or the combination of naproxen and simvastatin compared to placebo (adjusted p = 0.72). No statistically significant drug-placebo differences were found in the PANSS subscales, CGI or BACS between all groups. There was a near significant improvement in negative symptoms (p = 0.06), and an analysis of the 5 factor PANSS factors analysis found a significant improvement in simvastatin above placebo in withdrawal (p = 0.03). These finding were not significant after correcting for multiple comparisons. A meta-analysis on changes in total PANSS scores in studies on statins in schizophrenia, including the present study together with six other studies showed a significant improvement for statins compared to placebo (Hedges’ G of -0.245 (CI= -0.403, -0.086, p = 0.002). When one outlying study which showed particularly strong effects of statins was removed, part of the effect went away. In conclusion, in this study, naproxen and simvastatin alone or in combination were not efficacious in the treatment of symptoms in schizophrenia. However, the meta-analysis of all studies of simvastatin for schizophrenia indicates further research on this topic.