Purpose: To assess whether nonneoplastic Bcl-2/IgH rearrangements act as a confounding factor in the setting of minimal residual disease analysis by evaluating their incidence in a panel of lymphoma-free subjects, including cancer-free donors and chemotherapy-naive and chemotherapy-treated cancer patients. Patients and Methods: A total of 501 nonlymphoma subjects have been assessed: 258 cancer-free patients and 243 patients with malignancies other than lymphoma, 112 of whom were chemotherapy-naive. Patients were primarily assessed by nested polymerase chain reaction (PCR), followed by real-time quantitative PCR if they scored positive. In addition, six initially PCR-positive cancer-free donors were prospectively reassessed by qualitative and quantitative PCR after 30 and 60 days. Results: The overall incidence of Bcl-2/IgH positivity was 9.6%, with a median number of 11 rearrangements per 1,000,000 diploid genomes (range, 0 to 2,845 rearrangements), as assessed by real-time PCR. The incidence was similar in healthy subjects and cancer patients at diagnosis (12% and 12.5%; P = not significant). In contrast, the incidence of this translocation was only 2.3% in chemotherapy-treated patients (P < .001). In addition, three initially PCR-positive cancer-free donors showed persistence of their rearrangements when assessed after 30 and 60 days. Conclusion: The low incidence of nonneoplastic Bcl-2/IgH rearrangements following chemotherapy provides further evidence of the prognostic role of persistent PCR-positivity in the posttreatment molecular follow-up of follicular lymphoma patients.