External and seminested polymerase chain reaction techniques were used to determine B-cell clonality in paraffin-embedded biopsy specimens of abnormal lymphocytic infiltrates and malignant lymphomas of the gastrointestinal tract. Using consensus primers for the variable and joining regions, the authors detected clonal immunoglobulin heavy-chain gene rearrangements in five of eight endoscopic biopsy specimens (62.5%) and six of eight resection specimens (75%) of well-characterized B-cell gastrointestinal lymphomas. No clonal rearrangements were detected in 21 negative controls including 7 cases of chronic gastritis and 7 cases of Crohn's disease. In endoscopic biopsy specimens of eight patients with abnormal lymphocytic infiltrates, clonal immunoglobulin heavy-chain gene rearrangement was found in three of six cases (50%) in whom gastrointestinal involvement by lymphoma was subsequently established. Therefore, polymerase chain reaction may be used to demonstrate B-cell clonality in paraffin-embedded endoscopic biopsy specimens of abnormal lymphocytic infiltrates and may circumvent the need for more invasive procedures.