Kaposi's sarcoma (KS) develops more frequently in human immunodeficiency virus type 1 (HIV-1)-infected patients. In this study, we report that molecules released by CD8(+)CD28(-) T lymphocytes from HIV-1-infected patients promote endothelial-cell (EC) growth and induce ECs to acquire spindle cell morphology and upregulation of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular endothelial cell growth factor receptor-3 (VEGFR-3) (a typical feature of the KS cell phenotype). The effects observed on ECs cocultured with in vivo activated CD28(-) cells were partly reproduced when ECs were grown in medium containing interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). At concentrations similar to those found in the supernatant of in vivo activated CD28(-) cells, the two proinflammatory cytokines sustained EC growth and survival only when combined. We, therefore, conclude that CD28(-) T lymphocytes from HIV-1-infected patients exert their effect on ECs through a mechanism involving both IFN-gamma and TNF-alpha. This finding may have wide implications for our basic understanding of the immunopathology of KS.