The aim of the present study was to investigate the effects of Hypericum perforatum (St John’s wort) extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. A total of 18 healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg H. perforatum extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. During concomitant administration of low-dose oral contraceptive and H. perforatum there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (77%), and B (88%) than with oral contraceptives alone (35%). The area under curve (AUC) (0,24 h) and C_max of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC (0,24 h) and C_max of 3-ketodesogestrel decreased significantly from 31.2 ng/ml/h to 17.7 ng/ml/h and from 3.6 ng/ml to 3.0 ng/ml, respectively, during cycle A and by 41.7% and by 22.8% during cycle B, respectively, compared with the control cycle.