Objective To observe the clinical efficacy and safety of oral α-lipoic acid combined with methylcobalamin in treatment of diabetic peripheral neuropathy (DPN). Methods Sixty-four DPN patients were selected and randomly divided into experimental group (n=32) and control group (n=32). All the patients were given diet control, insulin or oral hypoglycaemic agent and the blood glucose was satisfactorily controlled; the original antihypertensive and antilipemic therapies were maintained. Meanwhile, patients in the control group were also given oral methylcobalamin (three times per day and each for 0.5 mg), and those in the experimental group were given oral α-lipoic acid (once a day and each for 600 mg) and oral methylcobalamin (three times per day and each for 0.5 mg) . The total symptom scores (TSS) and the nerve conduction velocity (NCV) were evaluated in the two groups before and 12 weeks after treatment; and the adverse drug reactions were also observed. Results The TSS and NCV were significantly improved in both groups after treatment compared with before treatment (P<0.05). After treatment, TSS was significantly lower in the experimental group than in the control group (P<0.05), and there were significant differences in the transmission velocities of the median motor nerve, nervus peroneus communis motor nerve and its sensory nerve between two groups (P<0.05). No serious side effects were found in the two groups during the treatment. Conclusion Oral α-lipoic acid combined with methylcobalamin on DPN is superior to methylcobalamin used alone for treatment of DPN, and the combined treatment is simple and has better patient compliance, making it worth popularizing.