BACKGROUND The combination of 8-methoxypsoralen with ultraviolet A exposure (PUVA therapy) is a standard treatment for a variety of dermatoses. The following three variants have been described: oral, bath, or cream PUVA. To achieve optimal therapeutic effects, ultraviolet A irradiation should be performed at the time of maximum photosensitivity, that is, at the time of maximum 8-methoxypsoralen tissue concentrations. METHODS To further specify this point of time, we assessed the concentration-time courses of 8-methoxypsoralen in the skin after oral, bath, and cream administration of 8-methoxypsoralen in a 3-way crossover microdialysis study of 8 healthy subjects. RESULTS Tissue concentrations after oral administration of 0.6 or 1 mg/kg 8-methoxypsoralen were low (peak plasma concentration range, 1.7-6.6 ng/ml) compared with topical administration for which maximum concentrations of 200 to 520 ng/ml and 720 to 970 ng/ml were achieved with 0.1% 8-methoxypsoralen cream and 3 mg/L 8-methoxypsoralen bath, respectively. Plasma concentrations after oral 8-methoxypsoralen, however, were up to 1000-fold higher than those found after topical application. With both topical applications, the tissue peak concentration uniformly occurred in the first 20 minutes after the end of the application time. In contrast, the time to reach the tissue peak concentration after oral administration ranged from 1 to 4 hours. CONCLUSIONS The time course of tissue concentrations corresponds closely with the time course of minimal phototoxic doses found in previous studies. Because tissue concentrations after topical administration of 8-methoxypsoralen (bath and cream) were high compared with plasma concentrations and because they were less variable and occurred at better predictable time points than those after oral administration, we suggest that topical PUVA is superior to systemic PUVA, at least from a pharmacokinetic point of view.