Background: Topical therapy may provide additional benefit in patients with painful diabetic neuropathy (PDN). This study was conducted to study the safety and efficacy of 0.025% capsaicin gel in this condition. Methods: A 20-week, double-blind, crossover, randomized, single-center study enrolled subjects with PDN. They received 0.025% capsaicin gel or placebo for 8 weeks, with a washout period of 4 weeks between the two treatments. Primary efficacy end point was percent change in visual analog scale (0-100 mm) of pain severity. Secondary outcomes were score change in Neuropathic Pain Scale (NPS), short-form McGill Pain Questionnaires (SF-MPQ), proportion of patients who had pain score reductions of 30% and 50%, and adverse event. Results: Of the 35 subjects screened, 33 were enrolled and 33 completed at least an 8-week treatment period. Intention-to-treat analysis showed no significant improvement in pain with capsaicin gel, compared with placebo with visual analog scale (VAS) score 28.8 mm vs. 34.6 mm (P = 0.53). No significant difference between the groups was found in SF-MPQ (7.4 vs. 7.71, P = 0.95), NPS (29.4 vs. 31.3, P = 0.81), and proportion of patients who had 30% or 50% pain relief. Capsaicin gel was well tolerated with minor skin reaction. Conclusions: 0.025% capsaicin gel is safe and well tolerated, but does not provide significant pain relief in patients with PDN. © 2012 The Authors Pain Practice © 2012 World Institute of Pain.