OBJECTIVES: To compare the costs of treating osteoarthritis (OA) pain using combination tramadol/paracetamol tablets, Non-Steroidal Anti-Inflammatory Agents (NSAIDs) alone or NSAIDs plus proton pump inhibitors (PPIs) from the perspective of the Spanish National Health System. METHODS: A decision-analytical model was constructed to analyse the cost outcomes of the three treatment strategies over 6 months. A cost-minimisation approach was used, which considered data related to resource utilisation, medication costs and costs for the treatment of adverse events. Data, derived mainly from the clinical literature, were supplemented by inputs from a Delphi panel as well as official price and tariff lists. The base-case analysis considered direct medical costs, including those for treating gastrointestinal (GI) and cardiovascular (CV) adverse events. Separate scenario analyses explored costs of NSAID-based regimens when renal events attributable to NSAIDs were considered. Univariate sensitivity analysis and scenario analysis considering different levels of adverse events, risk and adverse events costs where also carried out. RESULTS: In the base-case analysis, costs for 6 months´treatment of OA pain using tramadol/paracetamol were €232.86 compared with €274.60 for NSAIDs + PPIs and €133.75 for NSAIDs alone. This provided a cost saving of €41.74 per patient over 6 months for tramadol/paracetamol compared with NSAIDs + PPIs and a cost increase of €99.11 compared with NSAIDs alone. When renal adverse events of NSAIDs were considered, tramadol/paracetamol was cost saving compared with all NSAID-based regimens (saving €140.02 vs NSAIDs alone, €280.86 vs. NSAIDs + PPIs). Sensitivity analysis confirmed these results using extreme values of probabilities and unit costs for all options. CONCLUSIONS: Tramadol/paracetamol is cost saving compared with NSAIDs + PPIs for the treatment of OA pain over a period of 6six months. Tramadol/paracetamol is also cost saving compared with treatment with NSAIDs alone if considering renal adverse events.