Background: Chronic lymphatic leukemia (CLL) is the most common hematological malignancy in adults presenting with varied clinical courses. There is an increased demand for establishing known prognostic factors for stratifying CLL patients. Aim of the work: To investigate the expression of soluble form of human leucocyte antigen-G (HLA-G) & CD 38 in CLL and to correlate our findings with a variety of clinical and laboratory variables. Patients and methods: The study included thirty newly diagnosed CLL patients. They were 18 males and 12 females with age ranged from 49–65 (a mean of 57.5 years old). Diagnosis of CLL was confirmed by flow cytometric immunophenotyping using standard lymphoma panel. CD38 expression was determined by flow cytometry. S. HLAG was measured by ELISA method. Results: Positive CD38 expression was significantly associated with lower Hb and platelets (p = 0.008 and 0.025 respectively) also with higher Beta2 microglobulin (p = 0.012). Soluble HLA G was positively correlated with the platelets count(r = 0.400, p = 0.02). Higher level of soluble form HLA-G was significantly more frequent in patients of 60 years or older (p = 0.001). The cumulative overall survival was 83.3%. Positive CD 38 expression was associated with significantly worse survival (p < 0.005). HB count < 10 gm/dl was associated with significantly worse survival (p < 0.001). Conclusion: CD38 expressions are considered powerful prognostic markers in predicting overall survival for Egyptian CLL patients and they should be assessed to decide the patient's therapy and to determine disease prognosis. Expression of soluble form of HLA-G in CLL patients by ELISA get no extra prognostic importance.