OBJECTIVES: Non-steroidal anti-inflammatory drugs (NSAIDs) increase vascular and gastrointestinal risks. These risks have not been described with chondroitin sulphate (CS). This study aims to evaluate the economic impact of osteoarthritis (OA) treatment with CS versus NSAIDs for the Public Healthcare System in Catalonia (Spain). METHODS: An economic model was developed to estimate the health and economic impact of ethical CS prescription due to the avoidance of gastrointestinal adverse events (GIAE) and coronary ischemic events (CIE) associated with NSAIDs. The estimated population with knee and hands OA was calculated from EPISER study, population official data (age ≥ 20 years) and a population-based drug utilization study in patients with OA. The annual probabilities of suffering GIAE and CIE with CS and NSAIDs were obtained from a systematic review of medical literature, published meta-analysis and previous economical study (VECTRA). Direct healthcare costs (€ 2015) included drug acquisition, GIAE and CIE management. Other adverse events associated with NSAIDs with economic impact (renal failure, ischemic stroke, liver failure) were not considered in the model. Deterministic sensitivity analyses of the extreme values of all variables were undertaken. RESULTS: It is estimated that each year 300,000 and 72,000 OA patients are treated with NSAIDs and CS, respectively, in Catalonia with a cost of 11 and 4 million euros. Because 72,000 OA patients are treated with CS instead of NSAIDs, 19,222 mild-moderate and 649 severe episodes of NSAID-related GIAE and 39 CIE episodes would be avoided annually. The annual savings by avoiding GIAE and CIE episodes is estimated at 6.2 million euros and €493,000, respectively. Sensitivity analyzes confirmed the robustness of the results. CONCLUSIONS: OA treatment with chondroitin sulphate could reduce the health care costs for the Public Healthcare System due to the decreased rate of gastrointestinal and cardiovascular adverse events compared with NSAIDs.