Psoriasis patients exposed to high cumulative doses of psoralen + ultraviolet A frequently exhibit so-called "psoralen + ultraviolet A keratoses" (i.e., hyperkeratotic lesions with varying degrees of histologic atypia). The exact causes and molecular mechanisms of psoralen + ultraviolet A keratoses however, are not clear. We therefore performed DNA mutational analysis of the tumor suppressor gene p53 (exons in psoralen + ultraviolet A keratoses from 10 long-term psoralen + ultraviolet A-treated psoriasis patients. We detected 39 p53 mutations in 16 of 28 psoralen + ultraviolet A keratoses (57%) and 18 Ha-ras mutations in 11 of 25 psoralen + ultraviolet A keratoses (44%). Of the 39 p53 mutations and 18 Ha-ras mutations, 22 (56%) and 13 (72%), respectively, were of the ultraviolet fingerprint type (C-->T or CC-->TT transitions at dipyrimidine sites); 13 (33%) and two (11%), respectively, occurred at potential psoralen-binding sites (5'-TpA, 5'-TpG, or 5'-TpT DNA sequences) and were potentially psoralen + ultraviolet A induced; two (5%) and three (17%), respectively, were of ambiguous origin (ultraviolet and/or psoralen + ultraviolet A); and two (5%) and none (0%), respectively, were of the "other" type, respectively. We conclude that (1) the frequent mutation of p53 and Ha-ras may play a key part in the formation of at least some psoralen + ultraviolet A keratoses; (2) environmental and/or therapeutic ultraviolet exposure may be a major cause of psoralen + ultraviolet A keratosis as most Ha-ras and p53 mutations are induced by ultraviolet light; and (3) psoralen + ultraviolet A itself plays a smaller, though direct, role in causing these mutations.