Background: Oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) is a highly effective therapy for psoriasis and many other skin conditions. It is carcinogenic. Previously we reported an increased risk of melanoma that first emerged 15 years after first treatment. Objective: Our purpose is to present additional data concerning the associations of previous exposure to PUVA, the passage of time, and the risk of malignant melanoma. Methods: We have prospectively studied a cohort of 1380 patients first treated with PUVA in 1975 and 1976. We have documented the occurrence of melanoma and in this report compare the observed and expected incidence of melanoma in this cohort, particularly melanomas developing since our earlier report (ie, after March 1996). Results: Since 1975, 23 patients have developed 26 invasive or in situ cutaneous melanomas. In an average of 2.25 years since our last report, we detected 7 additional invasive melanomas (incidence rate ratio, 8.4; 95% confidence interval, 3.4-17.3). Conclusion: Beginning 15 years after first exposure to PUVA, an increased risk of melanoma is observed in our cohort of PUVA-treated patients. This risk is greater in patients exposed to high doses of PUVA, appears to be increasing with the passage of time, and should be considered in determining the risks and benefits of this therapy. (J Am Acad Dermatol 2001;44:755-61.)