The blood pressure (BP) effects of naproxcinod and naproxen were assessed in an 8-week, double-blind, crossover study in 131 hypertensive patients aged 50 to 74 years. Patients received naproxcinod 750 mg twice daily or naproxen 500 mg twice daily, then the alternate treatment, each for 14 days, with placebo run-in/washout before each active treatment period and 24-hour ambulatory BP monitoring conducted before and after each active treatment period. Mean change from baseline in average 24-hour systolic BP (SBP) after 2 weeks of treatment numerically favored naproxcinod 750 mg twice daily (least-squares [LS] mean for naproxcinod minus naproxen: −1.6 mm Hg; P=.12). Post hoc analyses showed statistically significant SBP differences favoring naproxcinod for the 8 elapsed hours (LS mean: −4.4 mm Hg; P<.0001) and the 24 hours following morning dosing (LS mean: −2.4 mm Hg; P=.006). Naproxcinod may be a beneficial alternative for patients with osteoarthritis requiring nonsteroidal anti-inflammatory drugs. J Clin Hypertens (Greenwich). 2011;13:376–384. ©2011 Wiley Periodicals, Inc.