Hydrogen sulfide (HS) is a naturally occurring gasotransmitter with vasodilator and inflammatory modulating activity. Non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, diclofenac, and ibuprofen, are some of the most commonly used anti-inflammatory drugs available but exhibit significant side effects, particularly gastric damage, when used chronically. ATB-337 is a hybrid molecule of an HS donor and the NSAID diclofenac. In rats, diclofenac at 10-50 µmol/kg caused significant gastrointestinal damage, whereas no damage was observed with ATB-337 treatment at the same dose. ATB-337 at 50 µmol/kg does not promote leukocyte adherence to vascular endothelium, an effect observed with diclofenac treatment alone. COX-1 and COX-2 were inhibited with similar efficacy by diclofenac and ABT-337. An increase in expression of the pro-inflammatory mediator TNF-α, as well as, the adhesion molecules ICAM-1 and LFA-1 were not observed in rats treated with 50 µmol/kg ABT-337, effects seen with equimolar doses of diclofenac. These results indicate that HS-releasing derivatives of NSAIDs may prove to be more effective anti-inflammatory agents than traditional NSAIDs alone.