BACKGROUND: Carbohydrate antigen 125 (CA-125) is a glycoprotein produced by epithelial and mesothelial cells. Serum CA-125 can be elevated in many benign and malignant conditions in which these tissues are involved. METHODS: We measured serum CA-125 concentration in 112 patients with chronic lymphocytic leukemia (CLL) and evaluated their association with Binet stage, serum lactate dehydrogenase (LDH), beta2-microglobulin (beta 2-MG), CD38, 70-kDa zeta-associated protein (ZAP-70), immunoglobulin heavy-chain variable region (IGHV) mutated status and cytogenetic abnormalities. RESULTS: The high level of CA-125 was associated with advanced Binet stage (r = 0.463, p < 0.001), high level of LDH (r = 0.404, p < 0.001) and beta 2-MG (r = 0.274, p = 0.004), and unmutated IGHV status (r = 0.366, p = 0.009). Multivariate analysis showed that advanced Binet (p < 0.001) and unmutated IGHV status (p = 0.018) were risk factors for the high CA-125 level. In univariate analysis, treatment-free survival (TFS) and overall survival (OS) were affected by Binet stage (p < 0.001 and p = 0.042, respectively), LDH (p = 0.018 and p = 0.013, respectively), beta 2-MG (p = 0.006, TFS only), ZAP-70 (p = 0.031, OS only), CD38 (p = 0.003, OS only), the presence of del(17p13) or del(11q22.3) (p = 0.006 and p = 0.049, respectively), IGHV mutation status (p = 0.018 and p < 0.001, respectively) and CA-125 (p = 0.003 and p = 0.034, respectively). In multivariate analysis, only advance Binet stage (p < 0.001) was independent risk factor of shorter TFS. CD38-positive (p = 0.020) and unmutated IGHV status (p = 0.034) were independent risk factors of worse OS. CONCLUSIONS: The results support a high CA-125 level correlates significantly with many clinical features of advanced stage, poor prognostic factors, and worse TFS and OS. However, CA-125 is not an independent prognostic factor in patients with CLL.