Background/Aims: Disease-related anemia in chronic lymphocytic leukemia (CLL) occurs when the obvious causes are excluded while its pathogenesis is still obscure. We investigated its underlying mechanisms in 56 untreated patients with CLL. Methods: Bone marrow (BM) lymphocytic infiltration was estimated in trephine biopsies. Serum erythropoietin (EPO) and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. The potential of BM CD34+ to differentiate into erythroid cells was evaluated by methylcellulose-based assays and in liquid cultures supplemented with EPO, SCF, IL-3 ± TNF-α. The response of erythroid precursors to EPO ± TNF-α was assessed by detecting activated key proteins of EPO-EPO receptor signalling pathway using Western Blot and EMSA. Results: Bone marrow lymphocytic infiltration was not exclusively responsible for disease-related anemia and CD34+ cells were intrinsically capable of generating erythroid precursors. Also, no deficiency of serum erythropoietin (EPO) or defective intracellular response of erythroid precursors to EPO ± TNF-α stimulation was observed. Serum TNF-α levels were found increased in anemic CLL patients and TNF-α appeared to directly inhibit the erythroid development in early stages of erythropoiesis. Conclusion: We concluded that CLL-related anemia was not due to intrinsic defects of erythroid precursors, but might result from the direct suppressive effect of TNF-α on the erythroid production.