BACKGROUND: Previous economic evidence about interventions for schizophrenia is outdated, non-transparent and/or limited to a specific clinical context. AIMS: We developed a discrete event simulation (DES) model for estimating the cost-effectiveness of interventions in schizophrenia in the UK. METHOD: The DES model was developed based on the structure of previous models, populated with demographic, clinical and cost data from the UK, and antipsychotics' effects from recent network meta-analyses. We simulated treatment pathways for patients with first-episode schizophrenia including events such as relapse, remission, treatment discontinuation, cardiovascular disease and death and estimated costs (2020£) taking the National Health Service perspective and quality-adjusted life years (QALYs) over ten years. Using the model, we ranked ten first-line antipsychotics based on their QALYs and cost-effectiveness. RESULTS: Amisulpride was associated with the highest QALYs, followed by risperidone long-acting injection (LAI), aripiprazole-LAI (6.121, 6.084, 6.070, respectively) and others (5.947-6.058). The most cost-effective antipsychotics were amisulpride, olanzapine and risperidone-LAI, with total probability of rankings of 1, ≤2, ≤3, that is, 95%, 89%, 80%, respectively; meanwhile, the least cost-effective were cariprazine, lurasidone and quetiapine, with total probability of rankings of 10, ≥9, ≥8, that is, 96%, 92%, 81%, respectively. Results were robust across sensitivity analyses and influenced primarily by relapse relevant parameters. CONCLUSIONS: Our findings suggest amisulpride (or risperidone-LAI where oral treatment is inappropriate) as the best overall first-line option based on QALYs and cost-effectiveness. Our ranking may be used to guide decision-making between antipsychotics. Our model is open source and could be applied to the other settings.