Abstract: AIM To search for new derivatives of diclofenac (DC) having activity of the parent drug and lacking its undesirable effects. METHODS Coupling DC with NO donor 3,4-dibenzenesulfonylfuroxan through esterification and amidation, evaluating anti-inflammatory activity against xylene-induced mice ear swelling and carrageenan-induced rat paw edema, observing side effects in the rat gastrointestinal (GI) tract and assessing NO releasing ability both in vitro and in vivo. RESULTS Eleven new compounds (I_1-11) were synthesized, and the structures of I_-11 were determined by IR, ¹HNMR, MS and elemental analysis. Compared with DC, I_1-5 and I₉ showed no significant difference in anti-inflammatory activity against xylene-induced mice ear swelling. I₄ and I₅ showed potency comparable to DC in treatment of carrageenan-induced rat paw edema. In GI tract, only slight mucosa sulface erosion was found in both I₄ and I₅ treated rats, while deep ulcer was found in nitrofenac dosed rats and ulcer perforation was found in DC treated rats. Five of eleven rats treated with DC died, one of eight rats treated with nitrofenac died. However, no death was found in eight rats dosed with I₄ or I₅. The detection of occult blood in feces and hematology index also showed that the extent of GI tract bleeding in I₄ and I₅ treated rats was much less than that in both DC and nitrofenac treated rats. In addition, I₄ and I₅ released NO both in vitro and in vivo. CONCLUSION Benzenesulfonylfuroxan-coupled DC may possess potency comparable to DC and less GI side effect than DC.