Aims: To explore the effect and mechanism of 1, 25-(OH)(2)D-3 on Schwann cell apoptosis induced by advanced glycation end products. Main methods: Schwann cells, isolated from rodent sciatic nerve were incubated with AGE-modified bovine serum albumin(AGE) to mimic diabetic conditions and 1,25-(OH)(2)D-3 was used as protector. Cell apoptosis was detected by PI/Annexin-V staining, caspase 3 activity assay and western blotting for caspase 3 and PARP. The activation of protein kinase A (PKA) and nuclear factor kappa-B (NF-kappa B) was evaluated by western blot. Immunofluorescent staining was used for intercellular location of NF-kappa B. Cytokine secretion was evaluated by enzyme-linked immunosorbent assay. Key findings: Schwann cell apoptosis accelerated after incubating with AGE. However, if combining 1,25(OH)(2)D-3 with AGE, apoptosis decreased significantly. 1,25-(OH)(2)D-3 enhanced PKA activity, but inhibited AGE-induced nuclear translocation of NF-kappa B. Furthermore, PKA activator (8-bromoadenoside cyclic adenoside monophosphate, 8-Br-cAMP) or NF-kappa B inhibitor (caffeic acid phenethyl ester, CAPE) could reduce the apoptosis, decreased cleaved caspase 3 and cleaved PARP, suggesting the involvement of PKA and NF-kappa B pathways in the protection of 1,25-(OH)(2)D-3 on Schwann cells. Moreover, 8-Br-cAMP and CAPE could inhibit AGE-induced secretion of interleukin(IL)-1 beta, prostaglandin E2(PEG2) and cyclooxygenase 2(COX2). Interestingly, 8-Br-cAMP decreased phospho-NF-kappa B and inhibited nucleus translocation of NF-kappa B. It hinted at the regulation of PKA to NFKB. Finally, a pre-treatment of H-89 (an inhibitor of PKA) could block the protection of 1,25-(OH)(2)D-3 on cell apoptosis. In conclusion, 1,25-(OH)(2)D-3 could protect Schwann cell against AGE-induced apoptosis through PKA/NF-kappa B pathway. Significance: These findings provide experimental rationales for using vitamin D for diabetic neuropathy.