Kaposi's sarcoma (KS) is the most common malignancy associated with HIV- infection. Over the last decade, deaths due to KS have nearly doubled. Opportunistic infection, either alone or in combination with progressive KS, is the leading cause of death. HIV-associated immunosuppression is the basis for this high infection rate, underscoring the urgent need for new therapeutic strategies for AIDS-related KS which incorporate antiretroviral therapy. The purpose of this proposal is to evaluate the tat inhibitor, RO24-7429 in a phase II trial for its potential as both a therapeutic agent for AIDS-related KS and as an antiretroviral agent. The study will be conducted within the Eastern Cooperative Oncology Group and take advantage of its large demographically diverse patient population and extensive experience with clinical trials. The specific aims of this proposal are 1) to investigate an optimal dose of the tat inhibitor, RO24-7429, in patients with AIDS-related KS, and to evaluate the overall and complete response rate of RO24-7429 in these patients, 2) to evaluate its effect on quality of life of patients with AIDS- related KS, 3) to evaluate the antiretroviral activity of RO24-7429 by monitoring CD4 and CD8 lymphocyte subsets, p24 antigen levels, and levels of free virus; and evaluate the molecular effects of RO24-7429 by serially evaluating levels of HIV-1 proviral DNA, spliced tatmRNA and unspliced mRNA (gag) in peripheral blood mononuclear cells by quantitative PCR, and 4) to explore the relationship between the antineoplastic effect and antiretroviral effect of RO24-7429.