AIMS The covalent linking of non-steroidal anti-inflammatory drugs (NSAIDs) to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increasing anti-inflammatory and analgesic potency. We have tested the hypothesis that a H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. RESULTS ATB-352 was significantly more potent as an analgesic than ketoprofen, and did not elicit GI damage. Pretreatment with a cannabinoid receptor-1 antagonist (AM251) significantly reduced the analgesic effects of ATB-352. The CB-1 antagonist exacerbated GI damage when co-administered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB-1 antagonist. ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352. INNOVATION Ketoprofen is a potent analgesic, but its clinical use is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H2S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting the analgesic effectiveness.