The therapeutic use of piroxicam as a nonsteroidal anti-inflammatory agent is associated with the development of photosensitivity in less than 1% of patients. The eruption usually occurs within a few days of commencing treatment with the medication. This time course suggests a phototoxic reaction. Attempts to demonstrate the phototoxic effects of piroxicam in humans, laboratory animals, and in in vitro cell assays were unsuccessful. At high concentration, however, one metabolite of piroxicam was phototoxic in animal studies and in in vitro assays. A second metabolite was mildly phototoxic in laboratory animals. These results suggest a mechanism whereby piroxicam photosensitivity may be due to a metabolite preferentially formed or accumulated in affected patients.