Transcriptional deregulation of the Bcl-2 gene has been demonstrated to extend cell viability via an inhibition of apoptotic cell death. Chronic lymphocytic leukemia (CLL) cells are inherently susceptible to apoptosis during short-term culture. Because increased expression of the Bcl-2 gene has been reported in CLL, we sought to correlate Bcl-2 protein expression with the in vitro propensity towards apoptosis and also clinical outcome. Immunoblot analysis of Bcl-2 protein revealed interpatient variability with nine of 42 (21%) cases demonstrating similar or greater expression than a t(14;18) containing lymphoma cell line and 18 of 42 (43%) cases demonstrating a level of expression similar to or less than that seen in normal peripheral blood lymphocytes. Bcl-2 expression did not correlate with clinical features, or with apoptosis, as measured by an in vitro DNA fragmentation assay. However, analysis of survival in the 33 untreated patients revealed significant differences based on the level of Bcl-2 expression, with higher expression being an adverse feature (P<0.02). This data suggests that Bcl-2 is important in the pathogenesis and progression of CLL and that quantitation of Bcl-2 protein may provide useful prognostic information.