Background:Prostaglandin E1 (P) or methylcobalamin (M) treatment has been suggested as a therapeutic approach for diabetic peripheral neuropathy (DPN) in many clinical trial reports. However, the combined effects of 2 drugs still remain dubious.Objective:The aim of this report was to evaluate the efficacy of M plus P (M + P) for the treatment of DPN compared with that of P monotherapy, in order to provide a reference resource for rational drug use.Methods:Randomized controlled trials (RCTs) of M + P for DPN published up to September 2017 were searched. Risk ratio (RR), mean difference (MD), and 95% confidence interval (CI) were calculated and heterogeneity was assessed with the I2 test. Subgroup and sensitivity analyses were also performed. The outcomes measured were as follows: the clinical efficacy, median motor nerve conduction velocities (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV, and adverse effects.Results:Sixteen RCTs with 1136 participants were included. Clinical efficacy of M + P combination therapy was significantly better than P monotherapy (fifteen trials; RR 1.25, 95% CI 1.18–1.32, P < .00001, I2 = 27%). Compared with P monotherapy, the pooled effects of M + P combination therapy on nerve conduction velocity were (MD 6.29, 95% CI 4.63–7.94, P < .00001, I2 = 90%) for median MNCV, (MD 5.68, 95% CI 3.53–7.83, P < .00001, I2 = 94%) for median SNCV, (MD 5.36, 95% CI 3.86–6.87, P < .00001, I2 = 92%) for peroneal MNCV, (MD 4.62, 95% CI 3.48–5.75, P < .00001, I2 = 86%) for peroneal SNCV. There were no serious adverse events associated with drug intervention.Conclusions:M + P combination therapy was superior to P monotherapy for improvement of neuropathic symptoms and NCVs in DPN patients. Moreover, no serious adverse events occur in combination therapy.