OBJECTIVE To review the biologic origin, functional characteristics, and current and potential clinical applications of a novel marker of immune system activation, the soluble interleukin-2 receptor (sIL-2R). METHODS Studies reported since 1985 were identified by a computer search using MEDLINE as well as from bibliographies of published work. METHODS Sixty-two reports on the clinical applications of the sIL-2R, largely from peer-reviewed journals, were identified. These reports address the utility and significance of sIL-2R measurements in various conditions. Basic scientific investigations delineating the biochemical and molecular features of the human interleukin-2 receptor complex and the sIL-2R protein were reviewed. METHODS The validity of sIL-2R quantitation as an index of in-vivo immune system activation and its usefulness as a measure of disease activity and outcome were examined. RESULTS The quantitation of sIL-2R, a novel laboratory measure of in-vivo immune system activation, correlates reliably with disease activity in autoimmune inflammatory disorders, transplantation rejection, and specific infectious disorders. Markedly elevated serum sIL-2R levels are a particularly prominent feature of certain hematologic malignancies, such as human T lymphotropic retrovirus type I-associated adult T-cell leukemia and hairy cell leukemia, reflecting tumor burden and response to therapy. The sIL-2R level at disease onset may also reliably predict long-term prognosis in non-Hodgkin lymphoma, and it appears to provide an additional serologic measure in the assessment of clinical progression in patients with human immunodeficiency virus infection and the acquired immunodeficiency syndrome. CONCLUSIONS Studies have suggested that sIL-2R levels offer a rapid, reliable, and noninvasive measure of disease activity, response to therapy, and, in some cases, prognosis in a broad spectrum of conditions associated with T- or B-cell immune activation.