Glucocorticoid therapy has been linked to increased risk of development of Kaposi's sarcoma (KS), which has become epidemic among HIV-infected individuals. However, no experimental evidence is available to explain the role of glucocorticoid in KS biopathology. We investigated the direct effect of dexamethasone (Dex) on the growth of cultured KS cells derived from acquired immune deficiency syndrome (AIDS) patients (AIDS-KS). Dex significantly stimulated the proliferation of AIDS-KS cells. Moreover, simultaneous exposure to Dex and oncostatin M, a KS major cytokine, produced a dramatic synergistic effect on proliferation of AIDS-KS cell. This suggests an interaction between glucocorticoid and growth factor intracellular pathways in KS cells. The expression of glucocorticoid receptor protein and mRNA in AIDS-KS cell cultures was examined by radioimmunoassay and in situ hybridization, respectively. Compared with other well studied cell lines, AIDS-KS cells contain an unusually high level of glucocorticoid receptor protein, which is further upregulated by glucocorticoid treatment. RU-486, a glucocorticoid receptor antagonist, completely abolished the stimulatory effect of Dex and reduced the synergistic effect of Dex and oncostatin M on proliferation of AIDS-KS. These findings demonstrate that glucocorticoid stimulates directly the proliferation of AIDS-KS cells via the modulation of glucocorticoid receptor expression.