A reduced incidence or the regression of Kaposi's sarcoma (KS) has been described in HIV-infected patients treated with HIV-protease inhibitors (PI). We have recently demonstrated that PI block the angiogenesis and the development of KS lesions induced experimentally in vivo by the inoculation of angiogenic factors or human primary KS cells. These effects of PI occur at the same drug concentrations in plasma of treated individuals, and they are due to the inhibition of cell invasion and of the activation of matrix metalloprotease-2, an enzyme that is key to angiogenesis and tumor growth and invasion. Since PI also block the production of cytokines involved in KS initiation and maintenance, this anti-inflammatory activity of PI may also contribute to the anti-KS effects observed in treated individuals. Thus, by direct and indirect activities PI can simultaneously block several pathways involved in tumor growth, invasion or metastasis. These data indicate that PI should also be investigated and exploited for the therapy of KS and tumors of different histology occurring in non infected individuals.