Peripheral neuropathy is the most frequent neurological complication of human immunodeficiency virus (HIV)-1 infection and is commonly associated with the development of chronic pain. This open-label, 12-week pilot study assessed the efficacy, tolerability, and safety of a high-concentration capsaicin dermal patch (NGX-4010; capsaicin, 640microg/cm2, 8% w/w) to treat painful HIV-associated distal sensory polyneuropathy (DSP). Eligible patients had moderate-to-severe pain in both feet due to HIV-associated DSP or antiretroviral toxic neuropathy. Patients received a single 60-minute application of the investigational high-concentration capsaicin patch to the affected areas. The primary outcome measure was the mean percent change in numeric pain rating scale (NPRS) during weeks two to 12 postadministration. After a single 60-minute NGX-4010 application, the mean percent change from baseline in "average pain for past 24 hours" NPRS scores during weeks two to 12 was -40% (95% CI: -61%, -19%; P=0.0020). Similar results were observed for "worst pain for past 24 hours" and "pain now" scores. Eight of 12 patients (67%) were treatment responders (> or =30% pain decrease). Four of 12 patients (33%) experienced a > or =50% reduction in pain. Treatment was generally well tolerated. Treatment-associated pain was self-limited and could be managed with short-acting opioids. This study demonstrates that treatment of painful HIV-associated neuropathy with a single application of NGX-4010, a high-concentration capsaicin patch, was feasible, well tolerated, and associated with significant reduction in pain over the 12 weeks studied. No safety concerns were identified. Controlled studies of NGX-4010 for the treatment of painful HIV-associated neuropathy are warranted.