Patients with mature follicular B-cell lymphomas develop aggressive non-Hodgkin lymphomas (NHLs) during disease progression. It is controversial whether most diffuse large B-cell lymphomas (DLBCLs) and Burkitt lymphomas (BLs) emerge as de novo lymphomas or from an original follicular lymphoma. To distinguish clonally related populations in aggressive NHL, we studied the immunophenotypic features of 18 consecutive samples from 16 patients. Three flow cytometric patterns were distinguished: (1) a homogeneous neoplastic population of large B cells with phenotypic features of follicular center cells; (2) 2 atypical populations of B cells, small monoclonal B cells, and large B cells with loss of some surface antigens; and (3) 2 clonal populations of small and large B cells sharing the same light-chain isotype. The 3 flow cytometric patterns were observed, respectively, in de novo DLBCL and BL, transformation into BL, and transformation into DLBCL. Flow cytometric data can provide valuable information about the natural history of NHL.