OBJECTIVES: Conduct a systematic review in schizophrenia relapse prevention, using the same methodology as the recent National Institute for Clinical Excellence (NICE) Schizophrenia Clinical Guideline. METHODS: Systematic review of CENTRAL, EMBASE, MEDLINE, for double-blind RCTs with, amisulpride, aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone or zotepine,  (completed November 2008). Relapse and withdrawal data were extracted using individual trial definitions. Mixed treatment comparison using Markov Chain Monte Carlo simulation was conducted using a random effects model to estimate the risk of relapse, treatment discontinuation due to either intolerable adverse effects (DAE) or other reasons. Summary effect estimates are presented as Odd Ratios [OR] with 95% Credible Intervals (95%CrI) calculated versus placebo. RESULTS: Literature searching returned 488 papers that identified 18 RCTs that were of sufficient quality to be included in the analysis. Relapse analysis reported quetiapine (XR) followed by risperidone and zotepine as most effective: quetiapine (XR) (OR: 0.151, 95%CrI: 0.021, 0.52), risperidone (OR: 0.168, 95%CrI: 0.035, 0.52), zotepine (OR: 0.17, 95%CrI: 0.017, 0.69), olanzapine (OR: 0.225, 95%CrI: 0.081, 0.513), haloperidol (OR: 0.314, 95%CrI: 0.075, 0.89), ziprasidone (OR: 0.315, 95%CrI: 0.079, 0.85), paliperidone (OR: 0.362, 95%CrI: 0.058, 1.214), amisulpride (OR: 0.387, 95%CrI: 0.041, 1.497), apriprazole (OR: 0.518, 95%CrI: 0.09, 1.702). Amisulpride, olanzapine and ziprasidone reported lowest OR for DAE. Amisulpride, quetiapine (XR) and olanzapine reported lowest OR for withdrawal due to other reasons, respectively. The model was considered a good fit for relapse and discontinuation due other reasons but not for DAE. CONCLUSIONS: When NICE’s schizophrenia guideline was in production, quetiapine (XR) was not licensed in the UK and therefore excluded from the health economic model. However, it is now available and the above analysis suggests that treatment with quetiapine (XR) could potentially provide benefit in the management of schizophrenia relapse prevention. No firm conclusions can be made from the analysis DAE.