Patients with mucosa-associated lymphoid tissue (MALT) lymphoma often have multiple sites of disease at initial diagnosis or during the clinical course. The neoplasms at multiple sites are often presumed to be identical, indicating dissemination or relapse. However, evidence to support this presumption is usually not available. We compared IGH VDJ sequences in 4 patients with 2 sequential sites of MALT lymphoma. The specimen pairs were stomach and nasopharynx, stomach and lung, ocular adnexa and nasopharynx, and ocular adnexa and parotid gland. The median interval between biopsies was 4 months (range, 1-32 months). Monoclonal IGH gene rearrangement was detected in all cases. In 3 patients, the VDJ sequences were distinct; in 1 patient the 2 biopsy specimens shared the same clone. MALT lymphomas involving multiple sites in a patient are usually not clonally related but arise independently, likely due to chronic antigenic stimulation, inducing oligoclonal B-cell proliferations and eventually a dominant B-cell clone.