Previous studies have suggested oral 5-fluorouracil (5-FU) is unpredictably and erratically absorbed. We studied oral pharmacokinetics of 5-FU in 16 patients (aged 34-71 years) with severe recalcitrant psoriasis. Each patient received repeated single oral doses of 5-FU, each separated by 1 week. Doses were ascending (300, 600, 900, 1,200 mg/m2), and after the first 3 patients, doses were started at 600 mg/m2 and increased. Multiple blood samples were obtained after each 5-FU dose and plasma 5-FU concentration determined by HPLC. Response was determined by clinical assessment of skin thickening, redness, and scaling on upper and lower body and quantified as percent improvement. Among all patients total dose and total area under the plasma 5-FU concentration-time curve (AUC) was significantly related (r = 0.65; p less than 0.01). In contrast no relationship between either total 5-FU dose and response (r = -0.07) or AUC and response (r = -0.08) was identified. With each individual patient, total 5-FU dose and response were well correlated in 11 of 14 patients (r = 0.96, 0.92, 0.92, 0.97, 0.78, 0.85, 0.71, 0.89, 0.96, 0.76, 0.94) and less well related in 3 of 14 (r = 0.57, 0.51, 0.15). Similarly, cumulative 5-FU AUC and response were well correlated in 11 of 14 patients (r = 0.91, 0.84, 0.83, 0.91, 0.77, 0.86, 0.75, 0.93, 0.99, 0.74, 0.89) and less well related in the same 3 patients (r = 0.61, 0.40, 0.03). The relationship of the 5-FU dose and AUC was nonlinear with normalized dose: AUC 1.0 at the lowest dose for each patient, at 1.5 dose AUC was 3.4 times baseline, at 2.0 dose AUC was 5.3 times baseline, and at 3.0 dose AUC was 36 times baseline. In patients with recalcitrant psoriasis 5-FU is consistently absorbed into the systemic circulation with extent of absorption increased with increasing dose in a nonlinear manner. Evaluation of both total 5-FU dose and total 5-FU AUC indicates a clear within-patient dose and AUC:response relationship.