BackgroundDiscrepancies between the National Institute for Health and Care Excellence (NICE) schizophrenia guideline recommendations and current clinical practice in the UK have been reported.AimsWe aim to assess whether it is cost-effective to improve adherence to the NICE schizophrenia guideline recommendations, compared with current practice.MethodA previously developed whole-disease model for schizophrenia, using the discrete event simulation method, was adapted to assess the cost and health impacts of adherence to the NICE recommendations. Three scenarios to improve adherence to the clinical guidelines were modelled: universal provision of cognitive–behavioural therapy for patients at clinical high risk of psychosis, universal provision of family intervention for patients with first-episode psychosis and prompt provision of clozapine for patients with treatment-resistant schizophrenia. The primary outcomes were lifetime costs and quality-adjusted life-years gained.ResultsThe results suggest full adherence to the guideline recommendations would decrease cost and improve quality-adjusted life-years. Based on the NICE willingness-to-pay threshold of £20 000–£30 000 per quality-adjusted life-year gained, prompt provision of clozapine for patients with treatment-resistant schizophrenia results in the greatest net monetary benefit, followed by universal provision of cognitive–behavioural therapy for patients at clinical high risk of psychosis, and universal provision of family intervention for patients with first-episode psychosis.ConclusionsOur results suggest that adherence to guideline recommendations would decrease cost and improve quality-adjusted life-years. Greater investment is needed to improve guideline adherence and therefore improve patient quality of life and realise potential cost savings.