To test the non-lipid-lowering effects of simvastatin on the response to injury in normolipidemic and hyperlipidemic mice. Wild-type (WT) mice (n= 40) and hyperlipidemic apolipoprotein-E-deficient (apoE–/–) mice (n= 40) received normal chow or chow containing simvastatin 100 mg/kg/day prior to bilateral femoral artery wire injury. Intimal hyperplasia and plasma cholesterol concentration were quantified after 4 weeks. Plasma cholesterol in WT mice treated or untreated with simvastatin was similar (100.9±6.6 vs. 94.3±17.5 mg/dl). Simvastatin did not affect intimal hyperplasia. In apoE–/–mice, intimal hyperplasia was increased 2.3-fold relative to WT mice (17,090±4,998 vs. 39,490±16,190; p< 0.001). In apoE–/–mice, simvastatin caused a paradoxical increase in plasma cholesterol (1,094±60.3 vs. 658±66.8 mg/dl; p< 0.001), confirmed by FPLC. This was associated with a further increase in intimal area (39,490±16,190 vs. 55,420±22,590 mm 2; p< 0.01). (1) Simvastatin had no effect on plasma cholesterol or the response to arterial injury in normolipidemic WT mice;(2) hyperlipidemia was associated with markedly increased intimal hyperplasia, and (3) simvastatin treatment of apoE–/–mice caused paradoxical hyperlipidemia and increased intimal hyperplasia.