OBJECTIVE: To investigate the analgesic effect of transcranial direct current stimulation (tDCS) over the primary motor (M1), dorsolateral prefrontal cortex (DLPFC), and sham tDCS in patients with painful diabetic polyneuropathy (PDPN). METHODS: Patients with PDPN (n=60) were divided randomly into the three groups (n=20 per group). Each group received anodal tDCS with the anode centered over the left M1, DLPFC, or sham stimulation for 20 minutes at intensity of 2 mA for 5 consecutive days. A blinded physician rated the patients' pain using a visual analog scale (VAS), Clinical Global Impression (CGI) score, anxiety score, sleep quality, Beck Depression Inventory (BDI), and the pain threshold (PT) to pressure. RESULTS: After the tDCS sessions, the M1 group showed a significantly greater reduction in VAS for pain and PT versus the sham and DLPFC groups (p<0.001). The reduction in VAS for pain was sustained after 2 and 4 weeks of follow-up in the M1 group compared with the sham group (p<0.001, p=0.007). Significant differences were observed among the three groups over time in VAS for pain (p<0.001), CGI score (p=0.01), and PT (p<0.001). No significant difference was observed among the groups in sleep quality, anxiety score, or BDI score immediately after tDCS. CONCLUSION: Five daily sessions of tDCS over the M1 can produce immediate pain relief, and relief 2- and 4-week in duration in patients with PDPN. Our findings provide the first evidence of a beneficial effect of tDCS on PDPN.