BACKGROUND. Non-steroidal anti-inflammatory drugs are associated with poor upper gastrointestinal (UGI) tolerability and increased ulcer risk, but patient adherence to gastroprotective co-therapy is frequently inadequate. A fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg was evaluated: efficacy is reported by Hochberg et al. (Curr Med Res Opin 2011;27:1243-53); tolerability findings are reported here. PATIENTS AND METHODS. In two 12-week double-blind, placebo-controlled, multicenter, phase III studies (PN400-307 and PN400-309), patients aged ≥ 50 years with symptomatic knee osteoarthritis randomly (2:2:1) received naproxen/esomeprazole magnesium BID, celecoxib 200 mg QD, or placebo. Tolerability end-points included: modified Severity of Dyspepsia Assessment (mSODA); heartburn severity; and UGI adverse events (AEs). RESULTS. Overall, 619 (PN400-307) and 615 (PN400-309) patients were randomized; mSODA scores improved (baseline to week 12) in each group, with no significant treatment differences between naproxen/esomeprazole magnesium and celecoxib (95% CIs: PN400-307: -0.4, 1.9; PN400-309: -1.8, 0.6). Naproxen/esomeprazole magnesium-treated patients reported significantly more heartburn-free days versus celecoxib (95% CIs: PN400-307: 2.1, 12.7; PN400-309: 2.5, 13.4). UGI AE incidence (PN400-307: 17.3%; PN400-309: 20.3%) was similar between treatment groups. UGI AEs resulted in few discontinuations (< 4%, either study). CONCLUSIONS. Naproxen/esomeprazole magnesium has comparable UGI tolerability to celecoxib in patients with osteoarthritis.