Analyses for clonality in cases of Richter's syndrome have provided evidence for a clonal evolution of high-grade lymphoma in most patients, while in others an independent cellular clone seems to exist in the secondary neoplasm. Richter's syndrome with an isolated high-grade lymphoma of the stomach has been rarely reported in patients with pre-existing B cell chronic lymphocytic leukemia (CLL). We investigated four cases of CLL or lymphoplasmacytoid immunocytoma (LPIC) with development of a localized high-grade B cell lymphoma in the stomach. Southern blotting showed different rearrangements of the immunoglobulin light and heavy chain genes in the tumor cells of the low-grade lymphoma and the gastric tumor in two cases. Comparison of the DNA sequences of the CDR3 region of the immunoglobulin genes revealed different clones in another case. By means of chromosomal in situ hybridization, trisomy 3 was detected in two cases of high-grade lymphoma of the stomach, but not in the cells of the associated low-grade tumor. Our findings indicate that high-grade non-Hodgkin's lymphomas arising localized in the stomach of patients with CLL or immunocytoma are not clonally related to the pre-existing low-grade lymphoma and, therefore indeed, present true secondary neoplasms.