Abstract Objectives We investigated the effect of argirein on acute inflammation edema and examined that aquaporin 4 (AQP4), p66Shc and activating transcription factor (ATF-6) might be involved in carrageenan-induced rat paw inflammation and be reversed by argirein, rhein and indometacin, but not l-arginine. Methods Inflammation was produced by carrageenan injected into rat paw and treated orally with argirein (100 mg/kg), rhein (100 mg/kg), l-arginine (100 mg/kg) or indometacin (5 mg/kg). Inflammatory oedema and biomarkers were examined. Key findings Swelling was reduced by argirein, rhein and indometacin; argirein was more effective than rhein at 1 h following medication. Activation of AQP4, p66Shc, ATF-6, NADPH oxidase subunits p22phox, gp91phox and matrix metalloproteinase 2 (P < 0.01) was significant and was suppressed by arginine, rhein and indometacin but not by l-arginine. Conclusions Activated AQP4, endoplasmic reticulum stress and p66Shc were actively implicated in the inflammation and these were suppressed by argirein, and its activity is favorable due to synergism in combination with l-arginine.