Silymarin, one of the most popular herbal medicines, has been widely used for its hepatoprotective effects. This study investigates the effects of repeated dose of silymarin and its major ingredient, silibinin, on the pharmacokinetics of the antidepressant trazodone. Treatment groups included vehicle control group, concomitant silymarin at 1.0g/kg dose, and four 7-day repeated dose induction groups of 0.5 and 1.0g/kg silymarin and 0.175 and 0.35g/kg silibinin. Microdialysis coupled with high performance liquid chromatography (HPLC) was used to simultaneously monitor blood and bile concentrations of trazodone in the rats. Results indicate that pretreatment with an extremely high dose of 1.0g/kg silymarin significantly decreases trazodone's area under concentration curve (AUC), distribution half-life (t(1/2,alpha)), elimination half-life (t(1/2,beta)), and mean residence time (MRT). In conclusion, the present study finds no marked effects of silymarin and silibinin on the pharmacokinetics of trazodone under normal daily doses and the relative safety of taking the herb with trazodone.