We investigated the preventive efficacy of exogenous methylcobalamin on sciatic nerve IGF-1 expression down-regulation and peripheral nerve deficit under different conditions (hyperglycemia and duration) of experimental diabetes in rats. Hyperglycemia was induced with streptozotocin, and stratified by exogenous insulin into mild and severe conditions. Duration of diabetes was ranged from 2-12 weeks. A single dose of methylcobalamin was intramuscularly administrated. Three groups of rats were compared in this study: (i) control group (NC, n = 30); (ii) saline-treated control diabetic group (n = 30); and (iii) methylcobalamin-treated diabetic group (n = 30). The study demonstrated a progressive decrease of sciatic nerve IGF-1 mRNA and peptide contents, and peripheral nerve dysfunction in the saline-treated diabetics over 12 weeks in contrast to the normal control non-diabetics (P < 0.01-0.0025). The IGF-1 reduction was delayed, which was consistent with retardation in nerve velocity conduction and structural impairment, in the methylcobalamin-treated diabetics, especially with mild hyperglycemia and shorter duration as compared with the saline-treated diabetics (P < 0.05-0.01). No effect of methylcobalamin on blood glucose was shown in the treated groups. It is concluded that exogenous methylcobalamin delayed onset of diabetic peripheral neuropathy via up-regulation of neural IGF-1 gene expression, and a better neuroprotective effect could be achieved in the presence of good control of hyperglycemia, especially at early stage of diabetes.