The most important criterion in monitoring the treatment of patients with trophoblastic disease is the quantitative measurement of hCG levels. It is particularly important to have a sensitive hCG-detection procedure that reliably distinguishes low positive hCG levels from negative ones. Reliable monitoring of serum hCG levels minimizes unnecessary chemotherapy in patients entering remission and provides an early indication for additional chemotherapy if and when the hCG levels again become detectable. We evaluated a two-site monoclonal-antibody immunoradiometric assay (IRMA) for its reliability in the management of trophoblastic disease. The assay utilizes a solid-phase, monoclonal antibody that recognizes the alpha subunit of complete hCG and a 125I monoclonal antibody that recognizes the beta subunit. The minimal effective concentration of hCG detectable with the IRMA is 3-4 mIU/ml. The study population consisted of 6 choriocarcinoma patients, 49 hydatidiform mole patients, 37 patients being monitored after spontaneous abortion or blighted ovum and 80 patients in whom the possibility of trophoblastic disease was being ruled out. Each serum specimen was analyzed with the IRMA and in one or more of a number of different radioimmunoassays. The results were correlated with the patient's clinical course. Of the procedures evaluated, the IRMA was the most reliable in identifying trophoblastic-disease patients who required additional chemotherapy. Furthermore, the IRMA yielded no persistent low positive hCG values in patients without clinical evidence of trophoblastic disease. Therefore, the two-site IRMA is recommended for accurately distinguishing a clinically relevant low positive hCG level from an undetectable one.