Using a sandwich enzyme-linked immunosorbent assay (ELISA) we were able to detect a soluble form of the CD30 antigen (CD30s) in the supernatant of cell lines expressing membrane-bound CD30 and in T and B cells after transformation with human T-cell leukemia virus (HTLV-I) and Epstein-Barr-Virus (EBV). While CD30s was not found in 250 healthy controls, it was detected in the sera of patients with Hodgkin's disease (23/100), anaplastic large-cell (6/9), angioimmunoblastic (2/2) and one unclassified high-grade non-Hodgkin's lymphoma (NHL), as well as in 18/20 patients with acute adult T-cell leukemia (ATL, HTLV-I-positive). It was absent in a large number of patients with other high-grade NHL, all low-grade NHLs, acute or chronic leukemias and solid tumors. The only non-malignant disease with detectable levels of CD30s was infectious mononucleosis (9/10). The membrane-bound form of CD30 has a molecular weight of 120 kDa. Western blot analysis revealed that CD30s in the serum of patients has a molecular weight of 88 kDa, identical to the antigen released by cell lines in vitro. CD30s disappeared in all originally positive cases after successful treatment and reappeared in relapsing patients. Thus, CD30s may be useful as a specific marker for disease activity of certain types of lymphoma and ATL.