Abstract: Objective To evaluate the efficacy and tolerability of a flexible-dose pregabalin regimen in patients with refractory painful diabetic peripheral neuropathy.Methods A prospective, open, non-randomized design was adopted. A series of 48 patients with refractory painful diabetic peripheral neuropathy received pregabalin 150 to 300 mg/d for 4 weeks. Pain intensity and sleep interference score were measured using numerical rating scale at baseline and at 2 and 4 weeks after therapy. Secondary measures for assessment of mood and overall efficacy included 17-item Hamilton depression scale (HAMD-17), Hamilton anxiety scale (HAMA) and patient global impression of change (PGIC). Adverse events were recorded.Results The 46 patients completed the 4 weeks study. The mean dose of pregabalin was (262.5±57.9)mg/d at endpoint. The mean pain score decreased from 6.2±1.0 at baseline to 4.3±1.4 at 2 weeks and 3.0±1.6 at 4 weeks (P all <0.01). The mean sleep interference score was 5.1±1.4, 3.3±1.4, 2.1±1.5 respectively (P all <0.01). Also, significant improvements were noted in the HAMD and HAMA score (P<0.01). And among them, 26 patients (56.5%) reported "very much improved" or "much improved" in PGIC. Pregabalin was generally well tolerated without severe side effects reported and only 2 patients (4.2%) discontinued the study because of their dizziness, somnolence.Conclusion Pregabalin 150 to 300 mg/d can effectively improve pain, sleep, anxiety/depression in patients with refractory painful diabetic peripheral neuropathy, and it was well-tolerated.