B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are regulators of normal B-cell development and survival. We investigated their role in chronic lymphocyticleukemia (CLL) by relating serum protein levels and CLL cell mRNA expression with clinical factors and disease progression. In patients with CLL, BAFF serum levels were significantly lower than in controls (0.64 ng/mL vs. 0.77 ng/mL, p = 0.014), and APRIL serum levels were significantly higher (4.10 ng/mL vs. 1.84 ng/mL, p = 0.041). CLL cells expressed BAFF and APRIL mRNA at lower levels than normal B-cells. Low BAFF serum levels were significantly correlated with a high blood lymphocyte count and advanced clinical stage, whereas APRIL levels were correlated with CD38 expression. In a multivariate analysis, the combined analysis of BAFF and APRIL serum levels emerged as an independent predictor of disease progression.