Polyreactive antibodies represent a significant fraction of immune repertoires and play an important role in the immune defense and immune homeostasis. Polyreactive B-cell receptors (BCR), however, are frequently expressed by B-cell lymphomas. It was suggested that polyreactive BCR on lymphoma cells might deliver stimulation signals by binding to various endogenous or exogenous antigens, thus promoting the survival of the malignant cells. In addition to natural polyreactive antibodies, immune repertoires contain antibodies that acquire polyreactivity after exposure to different redox-active substances such as reactive oxygen species, iron ions and heme. Here, we demonstrate that an antibody cloned from a patient's splenic marginal zone B-cell lymphoma acquires physiologically relevant binding affinity to various autoantigens following exposure to heme. We elucidated the mechanisms underlying polyreactive antigen binding. The results obtained in this study imply that antigen-binding receptors expressed on some malignant cells acquire polyreactivity after exposure to redox substances that are released at sites of inflammation or as a result of cellular damage. The acquisition of novel BCR specificities under hemolytic or inflammatory conditions may play an important role in the physiopathology of certain B-cell malignancies.