The distinction between benign florid lymphoid hyperplasia and low-grade gastric mucosal-associated lymphoid tissue (MALT) lymphoma may be a challenge. The presence of monoclonal B cells in Helicobacter pylori-chronic active gastritis has suggested that polymerase chain reaction (PCR) data should be viewed with caution. We investigated the reliability of PCR versus immunophenotyping in diagnosing early gastric MALT lymphoma. We studied 1511 biopsies from eight patients with high-grade primary gastric lymphoma, 25 with low-grade MALT lymphoma, 32 with atypical lymphoid infiltrates, and 39 with Helicobacter pylori-chronic active gastritis. Paraffin sections from all cases were stained with antibodies to CD20, CD3, AE1/AE3, kappa and lambda. PCR was performed on paraffin sections using the primer set VH-FR3/J(H). Using histopathology as the gold standard in diagnosis, we confirmed monoclonality in 22 of 25 MALT lymphomas (88%); a clonal band was found in 38% (15 of 39) of patients with chronic active gastritis. An immunophenotype pattern with predominance of CD20-positive cells in lymphocytic infiltrates was associated with monoclonality in 92% of cases. The presence of an enlarged irregular mantle zone was found in both monoclonal and polyclonal areas. An equal prevalence of B and T cells in lymphocytic infiltrates was associated with a polyclonal pattern in 24 of 31 cases (77%). Immunostaining of sIg (kappa and lambda) was difficult in paraffin sections and convincing proof of monoclonality was not obtained. Lymphoepithelial lesions were infrequent in gastric biopsies and their presence was highlighted with keratin stains. Because monoclonal B cells are observed in Helicobacter pylori-associated gastritis, the correct interpretation of clonality by PCR remains unclear. Paraffin section IHC using CD20 and CD3 is especially useful to confirm the diagnosis of gastric MALT lymphoma.