HIV-associated distal sensory polyneuropathy (HIV-DSP) is a painful condition with limited effective treatment. Capsaicin desensitizes cutaneous nociceptors resulting in reduced pain. We report a placebo-controlled study of a high-concentration capsaicin dermal patch (NGX-4010) for the treatment of painful HIV-DSP. This double-blind multicenter study randomized 307 patients with painful HIV-DSP to receive NGX-4010 or control, a low-concentration capsaicin patch. After application of a topical anesthetic, NGX-4010 or control was applied once for 30, 60, or 90 minutes to painful areas on the feet. The primary efficacy endpoint was percent change in Numeric Pain Rating Scale (NPRS) from baseline in mean "average pain for past 24 hours" scores from weeks 2 to 12. A single NGX-4010 application resulted in a mean pain reduction of 22.8% during weeks 2 to 12 as compared to a 10.7% reduction for controls (p = 0.0026). Following a transient treatment-related pain increase, pain was reduced; significant improvement was apparent by week 2 and continued throughout the controlled 12-week observation period. Mean pain reductions in the NGX-4010 30-, 60- and 90-minute groups were 27.7%, 15.9%, and 24.7% (p = 0.0007, 0.287, and 0.0046 vs control). One third of NGX-4010-treated patients reported >or=30% pain decrease from baseline as compared to 18% of controls (p = 0.0092). Self-limited, mild-to-moderate local skin reactions were commonly observed. A single NGX-4010 application was safe and provided at least 12 weeks of pain reduction in patients with HIV-associated distal sensory polyneuropathy. These results suggest that NGX-4010 could provide a promising new treatment for painful HIV neuropathy.