The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis accelerated by hyperglycemia. Our previous studies found that farnesyl pyrophosphate synthase (FPPS, EC 2.5.1.10), an essential enzyme in the mevalonate pathway, was upregulated in aorta media from diabetic mice along with the process of atherosclerosis. However, the exact role of FPPS in high glucose?induced proliferation of VSMCs is largely unclear. In our study, we found that alendronate (an FPPS inhibitor) attenuated diabetic accelerated atherosclerosis in?vivo and suppressed high glucose?induced VSMCs proliferation in?vitro. Moreover, in aorta from streptozotocin (STZ)?induced diabetic mice, 16?week treatment of alendronate decreased the activation of small GTPase (Ras, RhoA, and Rac1), but had no effect on the expression of cystathionine γ?lyase (CSE), the pivotal H2S?producing enzyme. Meanwhile, in VSMCs cultured in high glucose?containing media, alendronate remarkably decreased total CoQ content, increased the H2S level, depressed small GTPases (Ras, RhoA, and Rac1) activation, but yet had no effect on expression of CSE. In conclusion, FPPS inhibition by alendronate attenuated the high glucose?induced proliferation of VSMCs both in?vivo and in?vitro, probably though depressing H2S metabolism and suppressing small GTPases (Ras, RhoA, and Rac1) activation.