A multicenter study was conducted to establish the efficacy of topical 0.075% capsaicin cream in relieving the pain associated with diabetic neuropathy. Capsaicin or vehicle cream was applied to painful areas four times per day for 8 weeks in patients randomly assigned to one of two groups. Pain intensity and relief were recorded at 2-week intervals using physician's global evaluation and visual analog scales. Analysis at final visit for 252 patients showed statistical significance favoring capsaicin compared with vehicle for the following: 69.5% vs 53.4% pain improvement by the physician's global evaluation scale, 38.1% vs 27.4% decrease in pain intensity, and 58.4% vs 45.3% improvement in pain relief. With the exception of transient burning, sneezing, and coughing, capsaicin was well tolerated. Study results suggest that topical capsaicin cream is safe and effective in treating painful diabetic neuropathy.