In an open trial in 9 patients, we found that the ingestion of 500 mg of cysteine twice a day could prevent or lessen the photosensitivity associated with erythropoietic protoporphyria (EPP). We report here the results of a double-blind cross-over design trial in 16 patients. Patients with EPP were randomized into two groups, one that received 500 mg twice daily of cysteine during the first period and then placebo during the second period, and the second that received placebo first and then cysteine. Each drug ingestion period lasted 8 weeks, and there was a 1 week wash-out period between them. Patients were seen before the first period, at the end of the first period and at the end of the second period for phototesting, an objective method of assessing treatment efficacy, and for blood tests to monitor cysteine safety. The subjects also were asked to keep light-exposure diaries, a subjective method of assessing efficacy. We found that cysteine significantly prolonged the time it took to develop erythema by phototest, objectively demonstrating efficacy. In addition, analysis of patients' diaries showed that cysteine ingestion significantly increased the length of sun exposure it took to develop symptoms of photosensitivity. We conclude that cysteine ingestion may be an effective therapy in the prevention of photosensitivity associated with EPP.