Nonsteroidal anti-inflammatory drugs are associated with increases in blood pressure (BP), particularly in patients treated with antihypertensive therapy. Naproxcinod is a nitric oxide-donating cyclooxygenase inhibitor in development for osteoarthritis (OA). Thus, we characterized the effects of naproxcinod on BP in an integrated safety analysis of 3 pivotal trials of patients with OA of the hip or knee involving 2,734 patients. The changes from baseline in the systolic BP after 13 weeks of therapy with naproxcinod (375 and 750 mg), naproxen 500 mg (equipotent to naproxcinod 750 mg), or placebo twice daily were evaluated in all patients and in the subgroup taking renin-angiotensin system inhibitors. Heterogeneity testing showed no treatment-by-study interaction. The effects of naproxcinod 750 mg on the systolic BP was not different from placebo (mean change from baseline vs placebo −0.4 mm Hg, 95% confidence interval −1.6 to 0.8). Naproxen increased the systolic BP relative to placebo (mean change from baseline vs placebo +1.4 mm Hg, 95% confidence interval 0.1 to 2.7). In the renin-angiotensin system inhibitor–treated patients, the effect of naproxcinod 750 mg compared to naproxen 500 mg in the changes from baseline in the systolic BP was −4.3 mm Hg (95% confidence interval −8.5 to −0.0). In conclusion, naproxcinod had effects on BP similar to that of placebo in patients with OA. These results imply that naproxcinod would be less likely to alter systolic BP control in patients with OA than a conventional nonsteroidal anti-inflammatory drug, particularly in those treated with renin-angiotensin system inhibitor agents.