ATB‐346 is a hydrogen sulfide‐releasing non‐steroidal anti‐inflammatory drug (H2S‐NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti‐inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet‐killed Escherichia coli. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB‐346 was non‐inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB‐346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB‐346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti‐inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB‐346 is potently anti‐inflammatory and propose that ATB‐346 represents the next generation of H2S‐NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile. [ABSTRACT FROM AUTHOR]