Post-transplant patients undergoing prolonged Cyclosporine A (CsA) immunosuppressive therapy were reported to have an increased incidence of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. EBV-infected B cells cultured with CsA demonstrated increased EBV B-cell out-growth as compared to those cultured without CsA. Peripheral blood mononuclear cells (PBMC), following infection with EBV and CsA treatment, demonstrated increased IL-6 activity in the culture supernatant. The induction of IL-6 appeared to differ within the various lymphocyte populations. In monocytes and B cells, IL-6 expression was preferentially induced by EBV, and initiated by the binding of the two major virion glycoproteins, gp350 and gp220, to CD21, or a CD21-like receptor. Expression of IL-6 in T cells appeared to be due mainly to CsA. B cells also expressed IL-6 following EBV exposure, but not following CsA treatment. EBY-immortalized B-cell lines cultured with CsA exhibited both an increased number of cells expressing viral lytic-cycle antigens and increased amounts of lytic-cycle proteins. IL-6, which was induced by CsA in PBMC, was also capable of inducing the lytic viral cycle in several EBV-immortalized cells. When IL-6 was expressed, it was shown to act as an autocrine growth factor for B cells and to inhibit the immune system allowing for the promotion of B-cell tumors by impairing lymphokine-activated killer cells. Thus CsA treatment, in promoting both increased numbers of lytic EBV B cells and expression of the EBV paracrine growth factor, IL-6, within the microenvironment of EBV B:T cell and EBV B:monocyte interactions, may lead to increased EBV B-cell immortalization and ultimately result in the promotion of B-cell lymphomas in immunosuppressed patients.