There is considerable interindividual variation in bioavailability of Methoxsalen (8-methoxypsoralen) after ingestion of the standard dose used in photochemotherapy (psoralen plus ultraviolet A). A dose change may be used to alter the degree of photosensitivity, although there is limited information on the effect of 8-methoxypsoralen dose alterations on phototoxicity within individuals. We studied the effect of changes of 8-methoxypsoralen dose over a narrow range in 15 subjects with psoriasis. Two hours after ingestion, serum 8-methoxypsoralen concentration was determined and phototesting was performed at 350 +/- 30 nm (0.45-14 J per cm2). The minimal phototoxic dose at 72 h was recorded, erythema was measured using a reflectance instrument, and dose-response curves were constructed. Each subject was tested on three occasions using doses of 25 mg per m2 (conventional dose) or conventional dose +/- 10 mg. Median serum 8-methoxypsoralen concentration increased from 96 to 143 to 229 ng per ml with dose increases from conventional dose - 10 mg to conventional dose and conventional dose + 10 mg, respectively (p < 0.001). The median minimal phototoxic dose and D0.025 (the objective equivalent of the minimal phototoxic dose derived from the dose-response curve) were significantly reduced with increasing 8-methoxypsoralen dose from conventional dose minus 10 mg (minimal phototoxic dose 1.7 J per cm2; D(0.025) 2.8 J per cm2) to conventional dose (1.2; 1.4 J per cm2) and conventional dose plus 10 mg (0.9; 1.0 J per cm2) (p < 0.001). Change in 8-methoxypsoralen dose had no detectable effect on the maximum slope of the psoralen plus ultraviolet A erythema dose-response curve. Thus, 8-methoxypsoralen dose changes within individuals, over a narrow but clinically relevant range, significantly altered the threshold response to psoralen plus ultraviolet A erythema but not the rate of increase in erythema with increasing ultraviolet A dose.