The hydroxyl radical (.OH)-scavenging activity of d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), a novel nonsteroidal anti-inflammatory drug (NSAID), and that of several other NSAIDs were investigated by the hyaluronic acid (HA) degradation method and the electron spin resonance (ESR) spin-trapping technique. The superoxide anion (.O2-)-scavenging activity of M-5011 was also measured by the ESR technique. (1) M-5011 and the other NSAIDs examined inhibited the degradation of HA induced by the Fenton reaction system in a dose-dependent manner. (2) M-5011 and the other NSAIDs scavenged .OH directly in a dose-dependent manner. (3) M-5011 was the most potent drug among the NSAIDs tested regarding the scavenging activity of .OH as follows; M-5011 > indomethacin > ketoprofen = suprofen > aspirin. The .OH-scavenging activity of M-5011 was potent in comparison with that of oxidized glutathione (GSSG), an endogenous .OH scavenger. (4) M-5011 did not scavenge .O2-; nor did GSSG. These results suggest that M-5011 acts as a scavenger of .OH at sites with inflammatory lesions.