Since data concerning the toxicity and pharmacokinetics of concomitant repeated administration of grapefruit juice (GFJ) and simvastatin are lacking, we performed a chronic study in rats over a 4-week period using two different strengths (regular [RS] and double strength [DS]) of GFJ and two different doses of simvastatin (20 and 80 mg/kg, respectively). Both juices did not have a significant effect on the pharmacokinetic parameters of either simvastatin lactone (SVL) or its active metabolite simvastatin hydroxy acid (SVA) when administered concomitantly in a dose of 20 mg/kg over 28 days. However, when administered with 80 mg/kg simvastatin concentrations were elevated up to the last day of the study with DS-GFJ and to a lesser extent with RS-GFJ. Evaluation of toxicological parameters revealed a significant decrease in body and liver weights in groups receiving 20 mg/kg or 80 mg/kg simvastatin alone as well as in groups receiving simvastatin concomitantly with either DS- or RS-GFJ. No significant differences were detected for alanine (ALT) and aspartate (AST) aminotranferases in all groups. Chronic treatment with simvastatin significantly decreased plasma cholesterol levels (18 % for 20 mg/kg, 19 % for 80 mg/kg, respectively) as did coadministration of 80 mg/kg simvastatin with either RS-GFJ or DS-GFJ (33 %, 16 %). Interestingly, treatment with RS- or DS-GFJ alone significantly decreased plasma cholesterol levels by 22 % and 30 %, respectively. In conclusion, our results suggest that toxic effects in rats of concomitant intake of simvastatin and GFJ over 28 days are not more pronounced than those of simvastatin alone and that dose relationships between the administration of the juice and the drug may be important in determining the magnitude of the interaction.