The effect of human interferon (IFN) on the interleukin-2 receptor (IL-2R, p55) expression by peripheral blood mononuclear cells was investigated both in vitro and in vivo. IL-2R induction was assessed by the soluble IL-2R level in vitro and in vivo, which was measured by ELISA using two monoclonal antibodies to IL-2R(p55). Serum levels of sIL-2R increased significantly during IFN-alpha or IFN-beta therapy in 13 patients with chronic hepatitis B. When mononuclear cells were cultured with IFNs-alpha, -beta, or -gamma, the sIL-2R levels in the supernatant increased significantly. Dual flow cytometric analysis demonstrated that IL-2R was expressed on CD4+ and CD20+ mononuclear cells treated with IFN-alpha in vitro. CD4+ T cells and B cells may release sIL-2R when these cells are stimulated with IFN-alpha. RNA isolated from mononuclear cells treated with IFN-alpha contained increased levels of IL-2R-specific mRNA, as indicated by Northern blot analysis using an IL-2R-specific mRNA probe. These findings help to indicate how IFN plays a role in the regulation of the immune response, because IL-2R induction is known to be associated with lymphocyte activation.