The objective of this study was to investigate the effect of St. John's wort (SJW, Hypericum perforatum) on the pharmacokinetics of theophylline in healthy volunteers. Twelve healthy Japanese male volunteers participated in this randomized, open-labeled, crossover study. The subjects took an SJW caplet (300 mg) three times a day for 15 days. On day 14, they received a single oral dose of 400 mg of theophylline. They took the same dose of theophylline without SJW treatment on another occasion. Plasma and urine samples were obtained during a 48-hour period after theophylline administration. Theophylline concentrations in plasma and urine, as well as the major metabolites (13U, 1U, 3X) in urine, were measured. SJW caused no significant changes in the pharmacokinetics of theophylline in plasma. SJW administration tended to increase the ratio of 1U/the total amount excreted in urine. However, no changes in the ratio of unchanged theophylline, 13U, and 3X were observed. It is unlikely that the effect of 15 days of treatment with SJW on CYPs is sufficient to cause a change in plasma theophylline concentrations.