The nonsteroidal anti-inflammatory drugs (NSAIDs) have been repeatedly associated with photosensitivity reactions. The underlying mechanism however is not known, and the clinical features are not always consistent with either a phototoxic or a photoallergic mechanism. In this study, four NSAIDs were investigated for their phototoxicity potential in human volunteers using an oral dosing protocol. Phototoxicity, consisting of wheal-and-flare reactions following exposure to ultraviolet radiation, was demonstrated following the administration of naproxen and nabumetone, but was not seen in volunteers who received piroxicam, a drug reported to cause photosensitivity. Thus, although certain NSAIDs are potentially capable of producing phototoxicity reactions, others can presumably provoke clinical photosensitivity through other mechanisms.