Arthritis pain often occurs concurrently with hypertension and other cardiovascular risk factors. Treating patients with hypertension who have arthritis and other painful conditions can be a challenge because of potential risks associated with the agents commonly used to treat pain and inflammation. Hypertension is associated with endothelial dysfunction and decreased bioavailability of nitric oxide (NO). Naproxcinod, an investigational drug, is the first in a new class of agents called cyclooxygenase-inhibiting NO donators. They differ from traditional nonsteroidal anti-inflammatory drugs in their ability to donate NO, a signaling molecule known to have potentially beneficial effects on the vasculature and the gastrointestinal tract. Naproxcinod, by donating NO, offers a therapeutic option that might mitigate the negative blood pressure effects and adverse gastrointestinal effects associated with traditional arthritis therapies. This article reviews some preliminary preclinical and clinical studies of key safety data of an investigational new NO-donating anti-inflammatory agent.