The objective was to assess the cost-effectiveness of nonsteroidal anti-inflammatory agents (NSAIDs), NSAIDs with concomitant therapy to prevent gastrointestinal (GI) toxicity, and cyclooxygenase-2 specific inhibitors (COX-2) in the treatment of rheumatoid arthritis (RA). Markov (state-transition) models were used to simulate a cohort taking disease-modifying antirheumatic drugs, low dose steroid, and one of the following strategies: (1) NSAIDs without prophylaxis, (2) NSAIDs with misoprostol, (3) NSAIDs with proton-pump inhibitor (PPI), or (4) COX-2. Costs were measured in 1999 US dollars and health effects are expressed as quality-adjusted life years (QALYs). COX-2 was the most cost-effective strategy for preventing GI toxicity. The incremental cost/effectiveness (C/E) ratio between COX-2 and no prophylaxis was 56,751 dollar/QALY. Although COX-2 are the best option (among the strategies analyzed) to prevent GI toxicity, the incremental C/E ratio between COX-2 and no prophylaxis is higher than 50,000 dollar/QALY.