A systematic review of all clinical studies of Hypericum perforatum drug interactions was conducted. Eligible studies were prospective clinical trials evaluating the pharmacokinetic effect of H. perforatum on the metabolism of conventional drugs. Twenty-two pharmacokinetic trials studied an average of 12 (SD 5) participants; 17 trials studied healthy volunteers and five studied patients. Most (17) studies used a ‘before and after’ design; four studies used control groups other than the active group. Three studies randomised the sequence of administration or the participants to study arms or periods; three studies blinded participants or investigators. In 15 trials, investigators independently assayed the herb. Of 19 trials with available plasma data, three found no important interaction (change in area under the curve < 20%) and 17 found a decrease in systemic bioavailability of the conventional drug; in seven studies the 95% CI excluded a decrease of < 20%.