In follicular lymphoma, the t(14;18) status of the peripheral blood and bone marrow analyzed by polymerase chain reaction (PCR) is assumed to correlate with disease activity in patients with relapsed disease. The clinical significance of quantitating circulating lymphoma cells by real-time PCR is reported in patients on first-line treatment. Thirty-four consecutive patients with previously untreated follicular lymphoma and detectable t(14;18)-positive cells in pretreatment peripheral blood samples were monitored. All patients were treated with standard chemotherapy in combination with interferon alfa-2b. Before and after induction therapy, blood samples were taken for quantitative analysis of t(14;18). At presentation, a median of 262 t(14;18)-positive cells per 75,000 normal cells was found (range, 1-75 000). Patients with lower numbers of circulating tumor cells more frequently had bulky disease (P =.02). Seventy-nine percent of the patients responded clinically to treatment. In 22 of 28 patients, including 4 patients in whom treatment had failed clinically, the number of circulating t(14;18)-positive cells decreased to undetectable or low levels after therapy. In the remaining responding patients, circulating tumor cells persisted after therapy. These quantitative data on circulating t(14;18)-positive cells call into question the usefulness of molecular monitoring of the blood in a group of patients with follicular lymphoma uniformly treated with a noncurative first-line regimen. T(14;18)-positive cells decreased in peripheral blood after treatment, irrespective of the clinical response. Therefore, the significance of so-called molecular remission should be reconsidered in follicular lymphoma. (Blood. 2001;98:940-944)