Objective: To compare the rate of hospitalizations for serious upper and lower GI events in patients with increased GI risk taking a Traditional NSAID (tNSAID)+Proton Pump Inhibitor (PPI) or a COX-2 selective inhibitor (Coxib), chronic and acute. Methods: From the PHARMO Record Linkage System, including among others linked drug-dispensing and hospital records of approximately three million individuals in the Netherlands, we selected new users of Coxibs or tNSAIDs between January 1, 2000 and December 31, 2004. Eligible patients had =1 year history before the 1st NSAID dispensing and =1 year follow-up which ended at first hospitalization for serious GI event (the outcome), the last dispensing, or the end of the study period. Chronic users were defined as patients who used any NSAIDs for = 60 days during the first year of follow-up (n=58770); other NSAID users were acute users (n=538.420). Multivariate analysis by Poisson regression adjusted for sex, age, duration of follow-up, tNSAID and coxib dose, adherence to NSAIDs or PPIs, gastroprotection, anticoagulants, acetaminophen, corticosteroids, and cardiovascular disease. Results: The cohort included 52,953 new tNSAIDs+PPI users and 80,756 new Coxib users, with main characteristics: mean (±SD) age 58.1±15.5 vs. 56.7±17.5; female 55.3% vs. 62.2%; mean duration of treatment (days): 137±217 vs. 138±179, respectively. Among acute users, adjusted hazard ratios (95% Confidence Interval) of hospitalizations were 0.21 (0.14-0.32) for upper and 0.26 (0.16-0.42) for lower GI events, for Coxib versus tNSAIDs+PPI users. Among chronic users, adjusted hazard ratios were 0.35 (0.22-0.55) for upper GI and 0.43 (0.25-0.75) for lower GI events, for Coxib versus tNSAIDs+PPI users. Conclusion: Acute and chronic Coxib users had a statistically significantly lower rate of hospitalizations for upper and lower GI events compared to tNSAIDS+PPI users. Future research is needed to explain these findings, possibly due to prescribing for non-preventive reasons.