A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) ester prodrugs (NONO-NSAIDs) wherein a 1,3-dinitrooxy-2-propyl (12a-c), or O(2)-acetoxymethyl-1-[2-(methyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (14a-c), NO-donor moiety is directly attached to the carboxylic acid group of aspirin, indomethacin or ibuprofen were synthesized. NO release from the dinitrooxypropyl, or diazen-1-ium-1,2-diolate, ester prodrugs was increased substantially upon incubation in the presence of l-cysteine (12a-c) or rat serum (14a-c). The ester prodrugs (12a-c, 14a-c), which did not inhibit the COX-1 isozyme, exhibited modest inhibitory activity against the COX-2 isozyme. The NONO-NSAIDs 12a-c and 14a-c exhibited in vivo AI activity that was similar to that exhibited by the parent drug aspirin, indomethacin or ibuprofen when the same oral dose (micromol/kg) was administered. These similarities in oral potency profiles suggest these NONO-NSAIDs act as classical prodrugs that require metabolic activation by esterase-mediated hydrolysis. Hybrid NO-donor/anti-inflammatory prodrugs of this type (NONO-NSAIDs) offer a potential drug design concept targeted toward the development of anti-inflammatory drugs with reduced adverse gastrointestinal effects.