We investigated the association of plasma thrombopoietin (TPO) and overall survival in 127 patients with previously treated and previously untreated chronic lymphocytic leukemia (CLL). Higher levels of TPO were associated with advanced Rai stage (P < .001), higher levels of beta(2)-microglobulin (beta2-M) (P < .001), and the absence of mutation in the immunoglobulin heavy chain variable region (IgV(H)) (P < .001), and were inversely correlated with platelet count (P = .002). We found that TPO correlated strongly in a continuous manner with overall survival in both previously treated and untreated patients. The univariate Cox proportional hazard model demonstrated that high TPO levels were associated with shorter survival (P < .001), and multiple variable Cox proportional hazards regression analysis demonstrated that this was independent of the IgV(H) mutation status, beta2-M, and Rai stage. Recursive partitioning showed that a cutoff point of 639 pg/mL separated the CLL patients into 2 major survival groups (P < .001). The effects of beta2-M were masked by the effects of TPO in the patients with TPO levels higher than 639 pg/mL, but in the remainder, patients with beta2-M level higher than 4.95 mg/L had significantly shorter survival than those with lower values. Plasma TPO and beta2-M may be useful for the prediction of clinical behavior in CLL and may replace the need for the determination of IgV(H) mutation status.