Docosanol inhibits a broad spectrum of lipid-enveloped viruses in vitro including HSV-1, HSV-2, VZV, CMV, HHV-6, and HIV-1. These observations led us to conduct a pilot clinical study with docosanol 10% cream as a topical treatment for Kaposi's sarcoma (KS) in HIV-1-infected patients. In this open-label study 28 cutaneous KS lesions in 10 HIV-1-infected patients were treated topically five times daily for 4 weeks with evaluation of lesion characteristics of area, edema, and color. All patients elected to enroll in an extended treatment protocol and continued to treat for up to 35 weeks. Within 28 days, 2 of 10 patients exhibited a partial response based on standardized criteria exhibiting 74 to 83% reductions in total target lesion areas. With extended treatment, a partial response was exhibited in two additional patients where total target lesion area was reduced by 52% in one patient and target lesions in another patient that had been large, swollen, and painful at study initiation were no longer visible. No patient experienced disease progression or signs of visceral disease. The average percent decrease in lesion area for all target lesions was 20% (p < 0.01). A patient's response to therapy appeared to be independent of anti-HIV regimen, HIV viral load, or previous KS treatments. These results suggest that docosanol merits further investigation as a potential topical therapy in the treatment of AIDS-associated Kaposi's sarcoma lesions.