The endoscopic appearances of the gastrointestinal lymphomas differ widely, and it is often difficult to make the distinction between a benign lymphoproliferative disorder and a malignant lymphoma even with a histologic evaluation. Since almost all primary malignant lymphomas of the gastrointestinal tract are of B-cell origin, the confirmation of monoclonality in immunoglobulin (Ig) is helpful for differential diagnosis. Rearrangements of the Ig heavy chain gene were examined by polymerase chain reaction (PCR) analysis in frozen biopsy specimens of human stomach. The sensitivity of the analysis was sufficient to detect even a 5% clonal B-cell proliferation and results could be obtained within 17 h. In a clinical investigation, seven of eight cases (88%) of primary gastric malignant lymphoma showed a single band in polyacrylamide gel electrophoresis (PAGE) after PCR, suggesting a monoclonal proliferation of B-cell lineage. By contrast, all seven cases of reactive lymphoreticular hyperplasias showed a broad smear pattern in PAGE, which is thought to reflect polyclonal proliferation. None of the lymphocytes infiltrating around gastritis (7 cases), gastric ulcers (12 cases) and gastric carcinomas (15 cases) showed a monoclonal proliferation pattern. These findings suggest that detection of monoclonality in Ig heavy gene rearrangement by PCR is useful for the differential diagnosis of B-cell lymphoproliferative diseases in the gastrointestinal tract.