Objective: To investigate the effects of alpha-lipoic acid combined with mecobalamin on serum endothelial cell-specific molecule-1 (ESM-1), gamma-glutamyl transpeptidase (GGT) and oxidative stress in type 2 diabetic peripheral neuropathy (DPN). Methods: One hundred four patients with type 2 DPN treated in the department of endocrinology in hospital from March 2018 to May 2019 were randomly divided into the study group and the control group according to the random number table, with 52 patients in each group. Both groups were provided routine treatment such as blood glucose control, diet therapy and exercise guidance. The patients in the control group were treated with mecobalamin alone, while the patients in the study group were treated with alpha-lipoic acid combined with mecobalamin. Both groups were treated continuously for eight weeks. The clinical effects, serum endothelial cell-specific molecule-1 (ESM-1), the level of gamma-glutatnyl transpeptidase (GGT), the SNCV and MNCV changes of the median nerve and common peroneal nerve, the changes of oxidative stress indexes (superoxide dismutase [SODJ], malondialdehyde (MDA), glutathione peroxidase (GSH-Px) of the two groups were compared. Results: Clinical parameters in the study group were significantly improved in 94,23% of patients after treatment and 80,77% in the control group. The total effective rate in the study group was significantly higher than that in the control group (P<0,05). Compared with before treatment, the levels of ESM-1, GGT in both groups of patients decreased significantly, and ESM- 1, GGT levels in the study group was obviously lower than that in the control group (P < 0,01). The MNCV and SNCV of the median nerve and common peroneal nerve in both groups after treatment were significantly higher than those before treatment, and the study group was significantly better than the control group (P<0,05). After treatment, the levels of SOD and GSHPx in both groups were significantly increased compared to before treatment, and the level of MDA decreased markedly compared to before treatment. Moreover, the levels of SOD and GSH-Px in the study group were significantly higher than that in the control group, and the level of MDA in the study group was remarkably lower than that in the control group (P<0,05). Conclusion: alpha-lipoic acid combined with mecobalamin for the treatment of type 2 DPN can significantly reduce the level of ESM-1, GGT, reduce the body damage caused by oxidative stress, improve the nerve conduction velocity of patients and achieve better clinical efficacy.