In chronic lymphocytic leukemia (CLL), inhibition of spontaneous apoptosis determines a worse prognosis and increasing evidences show that disease progression relies also upon cycling CLL cells. We investigated bcl-2, as measure of apoptosis, and CD71, as measure of proliferation, by flow cytometry in 265 patients with CLL. Combining bcl-2 with CD71 values, we defined three subgroups: (1) bcl2 - CD71-; (2) bcl2 + CD71+; and (3) bcl2 + CD71- or bcl2- CD71+. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ (p < 0.00001) and in patients with bcl2 + CD71+ (p < 0.00001 and p = 0.02). The patients with discordant in bcl2 + CD71- and bcl2- CD71+ showed an intermediate outcome. Noteworthy, patients with bcl2 + CD71+ showed a shorter PFS within ZAP-70 negative subgroup (p = 0.00009). In multivariate analysis of PFS, age (p = 0.005), beta-(2) microglobulin (B(2)-M) (p = 0.003), bcl-2 (p = 0.004), CD49d (p = 0.001), and ZAP-70 (p < 0.001) resulted to be significant prognostic factors. The independent prognostic significance of B(2)-M (p = 0.009) and bcl-2 (p = 0.03) was confirmed within ZAP-70 negative patients. Bcl-2 and CD71 can be considered as interesting progression indicators, which should be validated in an independent cohort of patients, to take timely therapeutic decisions in CLL.