OBJECTIVE： To observe therapeutic efficacy and safety of flupentixol and melitracen combined with pregabalin in the treatment of painful diabetic peripheral neuropathy （PDPN）. METHODS： 150 cases diagnosed as PDPN were selected and randomly divided into control group A， control group B and combination group， with 50 cases in each group. All patients received basic therapy such as the control of blood glucose， blood pressure and blood lipid. Control group A was additionally given mecobalamine 1 mg added into 0.9％ Sodium chloride solution， qd， ivgtt， 2 weeks later， given Mecobalamine tablet 0.5 mg， po， tid； control group B was additionally given pregabalin 75 mg， po， bid； combination group was additionally given Flupentixol and melitracen tablet， 10 mg， bid， on the basis of control group B. 3 groups were given 4 weeks treatment. After treatment， VAS score， HAMD score， and SNCV and MNVC of median nerve and peroneal nerve were compared among 3 groups. Clinical efficacy and ADR were observed. RESULTS： After treatment， VAS score and HAMD score of combination group were significantly lower than control group A and B， with statistical significance （P＜0.05）. SNCV and MNCV of median nerve and peroneal nerve in combination group were significantly higher than in control group A and B， with statistical significance （P＜0.05）.The effective rate of combination group （90.0％） was significantly higher than that of control group A （56.0％） and B （74.0％）， with statistical significance （P＜0.05）. No serious ADR was found in 3 groups during treatment. CONCLUSIONS： Flupentixol and melitracen combined with pregabalin have definite therapeutic efficacy in the treatment of PDPN with good safety.