OBJECTIVE Patients with B-cell lymphoma can be induced to mount a specific immune response against the individual idiotypic determinants expressed in their tumor cells. This form of active immunotherapy is now under evaluation in the clinical setting. We evaluated the feasibility and effectiveness of this kind of immunotherapy in a group of patients with low-grade lymphoma, which included two cases of bi/triclonal lymphoma. METHODS Nine patients with a histopathologic diagnosis of follicular non-Hodgkin's (NHL) low-grade B-cell lymphoma were initially selected for this disease-free survival study. Idiotypic proteins were recovered by somatic fusion of the tumor cells and their identity with the tumor idiotype determined by molecular methods. The patients received the vaccine consisting of their tumor Ig protein coupled to keyhole limpet hemocyanine and were observed for toxicity, anti-idiotypic immune response, clinical outcome and circulating t(14;18)+ tumor cells. RESULTS The median duration of follow-up was 40 (10-64) months from the initiation of immunotherapy. Tumor regression was detected in two patients. No tumor progression was observed in the other patients. Eight patients generated specific anti-idiotypic antibodies and 3 out of five were cleared of circulating t(14;18)+ cells. CONCLUSIONS Induction of tumor-specific anti-idiotypic immune responses may be of benefit to patients affected by low-grade B-cell NHL. Our results are in line with those previously reported and call attention to the issue of tumor clonality in this kind of treatment.