Recently identified biological risk factors in B-cell chronic lymphocytic leukemia (B-CLL) include ZAP-70 and CD38 expression. The present study was conducted to clarify whether a combined analysis could improve predictive impact of these two parameters. We examined the expression of ZAP-70 and CD38 by flow cytometry method in 217 newly diagnosed, consecutive, unselected and well characterized B-CLL patients in relation to laboratory parameters and clinical outcome. We confirmed that both ZAP-70 as well as CD38 were independent of prognostic factors. There was a significant correlation between the percentage of leukemic cells positive for ZAP-70 and the percentage of CD38+CD19+ cells (R=0.629; p=0.000001). Combined analysis of ZAP-70 and CD38 showed concordant results in 158/217 patients (72.8%), while in 59 patients the results were discordant (27.2%). A mean treatment free survival (TFS) was the longest in ZAP-70-CD38-patients (45.6 months, comparing to 13.6 months in ZAP-70+CD38+ group). Also a mean overall survival was the longest in ZAP-70-CD38- patients (224.7 months compared to 77.9 months in ZAP-70+CD38+ patients).