Objective: 3-Hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors, or statins, have pleiotropic effects and can protect the vasculature in a manner independent of their lipid-lowering effect. Statins' effectiveness in reducing the risk of coronary events has been shown even in diabetic patients, and their effects on diabetic complications have been reported. Using a model of severe hindlimb ischemia in streptozotocin-induced diabetic mice (STZ-DM), we herein investigated the effects and mechanisms of statin therapy in diabetic angiopathy in ischemic hindlimbs. Methods and Results: STZ-DM mice frequently lost their hindlimbs after induced ischemia, while non-DM mice did not. Supplementation with statins significantly prevented autoamputation. We previously showed that diabetic vascular complications are caused by impaired expression of PDGF-BB, but statin therapy did not enhance PDGF-BB expression. Statins helped enhance endogenous eNOS expression. Furthermore, the inhibition of NO synthesis by administration of N-nitro-L-arginine methyl ester (L-NAME) impaired statins' ability to prevent STZ-DM mouse limb autoamputation, indicating that the therapeutic effect of statins in hindlimb ischemia in STZ-DM mice occurs via the eNOS/NO pathway. A combination therapy of statins and PDGF-BB gene supplementation was more effective for diabetic angiopathy than either therapy alone. Conclusions: These findings indicate that statin therapy might be useful for preventing intractable diabetic foot disease in patients with diabetic angiopathy.