Clonal rearrangements of the bcl-1 and bcl-2 protooncogenes are found in many B-lineage non-Hodgkin's lymphomas (NHL) and may play a role in their pathogenesis. We investigated rearrangements of the bcl-1 and bcl-2 protooncogenes in 13 cases of B lineage diffuse small cleaved-cell lymphoma (DSCL), and correlated the results with clinical history, immunophenotype, and outcome. Six cases showed bcl-2 rearrangements, including four patients with an antecedent follicular small cleaved-cell lymphoma (FSCL). Two patients had a bcl-1 rearrangement, including one with a previous FSCL. Of the five patients who lacked detectable bcl-1 or bcl-2 rearrangements, one had an FSCL history. Similar to the lack of correlation between clinical history and genotype, there was no correlation between genotype and immunophenotype. Our results indicate that although DSCL is a morphologically uniform disease, different molecular genetic pathways are involved in its genesis. Follow-up showed four of the six DSCL patients with bcl-2 rearrangements were alive with a median survival of 56 months, whereas the median survival of the seven patients lacking a bcl-2 rearrangement was 17 months and included only one survivor. Thus bcl-2 rearrangements in DSCL may define a patient subset with a more indolent genetic abnormality and prolonged survival.