Sunscreens containing 5-methoxypsoralen (5-MOP) are being promoted commercially to increase suntanning and sun protection. A recent study indicated that the 5-MOP concentration used in these sunscreens is too low to induce cutaneous phototoxicity with ultraviolet (UV) radiation. We investigated whether the sunscreen Sun System III (SS III), which contains 5-MOP, could induce skin erythema, edema, delayed pigmentation, and epidermal ornithine decarboxylase (ODC) activity when used in conjunction with UVA radiation (320–400 nm). ODC induction is an early event in the promotion of skin tumors. Increased epidermal ODC activity has been reported after exposure to UVB radiation (290–320 nm) alone and with topical 8-methoxypsoralen (8-MOP) plus UVA radiation. Using a solar simulator, we found SS III-induced erythema, edema, and epidermal ODC activity in hairless mouse skin with only 5 joules/em' of UVA. Human skin showed erythema and delayed pigmentation with SS III plus 20 joules/cm2 of UVA. No phototoxicity was seen in human skin unless the solar simulator output was filtered through water to reduce infrared radiation. This indicates that cutaneous phototoxic reactions to 5-MOP plus UVA are diminished by heat. Like 8-MOP, 5-MOP cross-links DNA and has the same skin photocarcinogenic potential as 8-MOP. Therefore the use of phototoxic psoralens in over-the-counter sunscreens is inappropriate because of the risk of increased UV-induced skin cancer.