Lymphomas of mucosal-associated lymphoid tissues (MALT) constitute a distinct clinicopathologic entity comprised of centrocyte-like cells with a characteristic morphologic appearance and immunophenotype. The origin of these cells is still undetermined, although evidence suggests that they might derive from marginal zone lymphocytes present in normal lymph nodes and spleens. Recently, marginal zone lymphomas have been shown to have a high rate of p53 mutation. To determine whether p53 mutations were also present in MALT lymphoma, we evaluated specimens from eight patients (six gastric specimens, one parotid, and one from the small bowel) for p53 mutations using polymerase chain reaction and single strand conformational polymorphism analysis. Exon-4 through exon-8 were evaluated, because these are common sites of p53 mutation. In addition, tissues from 15 patients with MALT (including seven studied by single strand conformational polymorphism analysis) were examined for expression of p53 gene protein product by immunohistochemical techniques. All specimens were negative for p53 mutations, suggesting that mechanisms of lymphomagenesis are different for MALT than for splenic marginal zone lymphomas. Despite the absence of p53 point mutations, p53 gene product was localized in tissues from three of 15 patients with MALT. Staining was restricted to nuclei of neoplastic cells and was present in less than 10% of the cells. In summary, low-grade MALT lymphomas differ from marginal zone lymphomas in lacking p53 point mutations, although some patients express low levels of p53 gene product.