Spindle-shaped cells of vascular origin are the probable tumor cells of Kaposi sarcoma (KS). These cells, derived from patients with KS and AIDS, proliferate in response to extracellular Tat protein of human immunodeficiency virus type 1. Normal vascular cells, believed to be the progenitors of AIDS-KS cells, acquire spindle morphology and become responsive to the mitogenic effect of Tat after culture with inflammatory cytokines. Such cytokines are increased in human immunodeficiency virus type 1-infected people, suggesting that immune stimulation (rather than immune deficiency) is a component of AIDS-KS pathogenesis. Here we show that (i) Tat promotes adhesion of AIDS-KS and normal vascular cells; (ii) adhesion of normal vascular cells to Tat is induced by exposure of the cells to the same cytokines; (iii) adhesion is associated with the amino acid sequence RGD of Tat through a specific interaction with the integrin receptors alpha 5 beta 1 and alpha v beta 3, although it is augmented by the basic region; and (iv) the expression of both integrins is increased by the same cytokines that promote these cells to acquire spindle morphology and become responsive to the adhesion and growth effects of Tat. The results also suggest that RGD-recognizing integrins mediate the vascular cell-growth-promoting effect of Tat.