To determine the potentially adverse effects of photoactive medications taken in conjunction with oral methoxsalen photochemotherapy (PUVA) for psoriasis, we studied the incidence of phototoxic reactions in 1,125 patients treated with PUVA at 15 centers. During the initial (clearing) phase of PUVA therapy, patients using photoactive medications were no more likely to have diffuse delayed erythema than patients who did not use such medications. After clearing, patients 45 years of age or older who used photoactive drugs were 2.3 times as likely to discontinue PUVA therapy for at least one month owing to problems related to UV-induced burns than were those who did not use such drugs. Only 6% of patients older than 45 years who took photoactive medications had problems with phototoxicity sufficiently severe to contribute to permanent discontinuation of PUVA therapy.