OBJECTIVES: In schizophrenia, medication adherence is critical to achieve better patient outcomes and to avoid relapses, which are responsible for a significant proportion of total healthcare costs for this chronic illness. The aim of this study was to assess the cost-effectiveness of olanzapine long-acting injection (OLAI) compared with risperidone long-acting injection (RLAI) in patients with schizophrenia in Spain. METHODS: A discrete event simulation (DES) model was developed from a Spanish healthcare system perspective to estimate clinical and economic outcomes for patients with schizophrenia over a five year period. Patients who had earlier responded to oral medication and have a history of relapse due to adherence problems were considered. These patients faced the option to be treated with either OLAI or RLAI. In the absence of a head-to-head clinical trial, discontinuation and relapse rates were obtained from an indirect comparison of open-label studies. The model accounted for age, gender, risks of relapse and discontinuation, relapse management, hospitalization, treatment switching and adverse events. Direct medical costs (year 2011) and outcomes including relapse avoided, life years (LYs), and quality-adjusted life years (QALYs) were discounted at a rate of 3%. RESULTS: When comparing RLAI and OLAI, the model predicts that OLAI would decrease 5-year costs by €2940, and results in a QALY and LY gain of 0.07 and 0.04, respectively. Patients on OLAI had fewer relapses compared to RLAI (1.39 vs. 1.82) and fewer discontinuations (1.22 vs. 1.71). Sensitivity analysis indicated that the study was robust and conclusions were largely unaffected by changes in a wide range of parameters. CONCLUSIONS: The present evaluation results in OLAI being dominant over RLAI, meaning that OLAI represents a more effective and less costly alternative compared to RLAI in the treatment of patients with schizophrenia in the Spanish setting.