The objective of this study was to determine possible effects and potential mechanisms of cardamonin on improving insulin resistance and vascular proliferative lesions in the rat's model system. Fed with 60% fructose-enriched diet for 12 weeks, male Sprague-Dawley (SD) rats developed insulin resistance and hyperinsulinemia. They also showed excessive proliferation of the vascular smooth muscle cells (VSMCs) and activation of the mammalian target of rapamycin (mTOR)/translation control proteins p70 ribosomal S6 kinase (P70S6K1)/eukaryotic initiation factor 4E binding protein 1 (4E-BP1) signaling in the rat thoracic aorta. From weeks 9-12, cardamonin was injected into the peritoneal cavity once daily. Under the detection of microscopy and electron microscopy, cardamonin improved hyperinsulinemia and inhibited proliferation of VSMCs in the thoracic aorta of rats in a dose-dependent manner. By the Real-Time RT-PCR, mRNA expression of mTOR, P70S6K1 and 4E-BP1 was significantly reduced in cardamonin treated rats. Similarly, protein over-expression of mTOR and p-P70S6K1 was obviously inhibited by immunohistochemical analyses. These findings suggest that cardamonin may play a role in ameliorating insulin resistance and smooth muscle hyperplasia of major vessels in fructose-induced rats, possibly via a mechanism that involves the modulation of insulin/mTOR signaling.