Background: Increased proliferation and survival of leukemic B-lymphocytes can be induced by CD69 overexpression, which resembles B cells at an earlier and larger stage of activation. This could potentially indicate an aggressive and progressive clinical outcome. Increased CLL stages, diffuse marrow infiltration, and a brief overall survival are linked to overexpression of CD69. The aim of our study was to identify the prevelance of CD69 in patients with chronic lymphocytic leukemia and its value as a predictor for prognosis. Subjects and methods: 50 newly diagnosed CLL patients were included. Immunophenotyping and detection of CD69, CD38 and CD200 expression by flowcytometry was performed. Results: There was a statistically significant relation between presence of positive CD69, CD38 expression level, and positive Del p17. There was a statistically significant positive correlation between CD-69 and CD-200, CD-38, spleen, liver diameters, and LN size. Regarding response to treatment, 20% showed no response, and there was a statistically significant relation between response and CD 69 (significantly higher in those with no response). By applying the ROC curve, the best cutoff of CD 69 in prediction of non-response is ≥58.15% with area under curve 0.958, sensitivity 90%, specificity 87.5%, positive predictive value 64.3%, negative predictive value 97.2% and overall accuracy 88%. There was a statistically significant association between time till response and expression of CD-69. All those with positive expression of CD-69 had significantly higher time till response. Conclusion: CD69 determined by flowcytometry could be considered a novel important independent prognostic parameter in B-CLL.