Objectives: Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. This retrospective study is planned to assess the prognostic value of serum free light chain (sFLC) levels and FLC ratio (FLCR) in CLL. Methods: Quantitative levels of sFLC were measured nephelometrically in sera collected at diagnosis. The expressions of ZAP70 and CD38 were quantified by flow cytometry. Chromosomal abnormalities were determined by interphase fluorescence in situ hybridization (FISH). Results: In a cohort of 101 patients with a median follow-up of 29 (1-234) months, sFLC levels were found to be high in 55 patients (54.5%). An abnormal FLCR was found in 30 patients (29.7%). FISH-based genetic risk groups did not differ significantly with respect to sFLC and FLCR (P > 0.05). Median time to first treatment was shorter in patients with high sFLC levels (P = 0.02). Median overall survival (OS) was shorter in patients with high sFLC levels (P = 0.01) and abnormal FLCR (P = 0.05). In patients with early stage disease, median OS was shorter in high sFLC (P = 0.03) and abnormal FLCR groups (P = 0.048). A relationship was observed between abnormal sFLC levels and CD38 positivity on logistic regression analysis (P = 0.003; OR: 4.44; 95% CI: 1.66-11.8). Conclusions: This study highlighted the adverse prognostic impact of high sFLC levels and abnormal FLCR with regard to survival in CLL, even in early stage patients. Prospective studies are warranted to validate the adverse impact of sFLC and FLCR on clinical outcome.