Lymphocyte activation induces production of soluble IL-2 receptor (sIL-2R) which is a large portion of the CD25 membrane molecule and which is detectable in serum. Serum sIL-2R is reported here to increase as a direct effect of the HIV infection and not to be due to secondary opportunistic infections. sIL-2R increased promptly after HIV seroconversion in 83% of 50 initially seronegative homosexual men. The sIL-2R serum levels stabilized in the third year after seroconversion and were then predictive of later CD4 T cell levels and development of AIDS. In two studies of 59 and 395 seropositive men, beta-2 microglobulin (B2M) and neopterin levels in serum correlated closely with each other but not with sIL-2R levels. Thus, increased production of sIL-2R may reflect pathological processes distinct from those determining B2M and neopterin increases. Membrane CD25 expression on peripheral blood lymphocytes, unexpectedly, was found to be decreased in HIV infection. This contrasted with the increased sIL-2R in serum. Investigations with sensitive flow cytometry technics showed that CD25 was expressed at reduced levels and averaged only 12% of lymphocytes from HIV-infected individuals in contrast to 25% in noninfected individuals. All major lymphoid populations showed reductions in CD25 positive cells. This reduction in lymphoid membrane CD25, however, was not inversely correlated with the increased serum levels of sIL-2R or with other parameters of immune deficiency or activation. Thus, surface CD25 loss and serum sIL-2R increase are separate and independent consequences of HIV infection.