Naproxen (NAP) is a potent nonsteroidal anti-inflammatory drug (NSAID) with a favorable cardiovascular profile. However, its long-term use may lead to serious gastrointestinal and renal side effects. NOSH- (nitric oxide and hydrogen sulfide) releasing naproxen (NOSH-NAP, AVT-219) belongs to a new class of anti-inflammatory agents designed to overcome these limitations. We compared the gastrointestinal safety, anti-inflammatory, analgesic, antipyretic, and antiplatelet properties of AVT-219 to that of NAP in preclinical animal models. We also evaluated its anticancer effects in 11 human cancer cell (HCC) lines of six different tissue origins and in a chemotherapeutic xenograft mouse model of colon cancer. AVT-219: (1) was orders of magnitude more potent than NAP in inhibiting the growth of cultured HCC; (2) was safe to the stomach, whereas NAP caused significant ulceration; (3) showed strong anti-inflammatory, analgesic, antipyretic, and antiplatelet properties comparable to NAP; and (4) NAP caused a significant rise in plasma tumor necrosis factor-alpha (TNFa), whereas in the AVT-219-treated rats this rise was significantly less. Mechanistically, AVT- 219 was a strong antioxidant, inhibited cyclooxygenase (COX)-1 and -2, thus reducing prostaglandin (PG) E2. In xenografts, AVT-219 significantly reduced tumor growth and tumor mass with no sign of GI toxicity, whereas NAP-treated mice died due to GI bleeding. AVT-219 displayed considerable safety and potency in inhibiting HCC growth; was an effective analgesic, antipyretic, antiplatelet, and anti-inflammatory; and was significantly more efficacious than NAP in reducing the growth of established tumors in a xenograft mouse model.