ATB-346 is a non-steroidal anti-inflammatory drug (NSAID), derived from naproxen but coupled to an H2S-releasing moiety. At 30 µmol/kg in rats, it suppressed COX and gastric PGE2 synthesis to the same level as naproxen but reduced COX-2 expression and accelerated recovery in a rat spinal cord injury model. It also provided enhanced anti-inflammatory and antinociceptive activity over naproxen in a rat model of arthritis. ATB-346 does not induce gastrointestinal toxicity and, in contrast to other NSAIDs, it accelerated healing of pre-existing gastric ulcers. Studies of ATB-346 have shown promising results in vitro and in animal models of melanoma and intestinal tumorigenesis. A Phase I clinical trial in Canada did not find any significant gastrointestinal, cardiovascular, renal, or hematological findings across dose ranges in healthy adults (25 mg–2,000 mg once/d). A Phase II trial in Canada is ongoing for patients with osteoarthritis of the knee.