Tumor necrosis factor (TNF)-α and interleukin (IL)-10 are cytokines involved in the balance between cell-mediated and humoral immunity. We investigated whether serum TNF-α and IL-10 levels have any impact on clinical outcome of patients with chronic lymphocytic leukemia (CLL). TNF-α and IL-10 levels were determined in the serum of 160 CLL patients at the time of diagnosis. The cytokine low-risk group consisted of patients with either TNF-α and IL-10 levels below their medians or those with only one elevated parameter. Both TNF-α and IL-10 levels greater than or equal to their medians defined the cytokine high-risk group. The high-risk patients presented a shorter 3-year treatment-free survival (TFS) than low-risk subjects (15 vs. 69.6 %; p < 0.0001). The high-risk group (p = 0.0002) along with high leukocyte count (p < 0.0001) and unmutated immunoglobulin heavy-chain variable region genes (p < 0.0001) independently predict the risk of progression in patients with Rai stage 0-II. Furthermore, the high-risk group had an independent prognostic impact on shorter TFS both in patients with mutated (24.3 vs. 78.2 %; p < 0.0001) and unmutated (8.2 vs. 49 %; p = 0.004) immunoglobulin heavy-chain variable region genes (IGHV) as compared to the low-risk group. The estimated 5-year overall survival (OS) of high-risk patients was shorter than those in the low-risk group (83.3 vs. 97.1 %; p = 0.003). Multivariate analysis demonstrated the cytokine high-risk group (p = 0.02) followed by Rai stage III-IV (p = 0.048) to be independent factors predicting shorter OS. At diagnosis, TNF-α and IL-10 may predict the outcome of patients with CLL.