Background: In chronic lymphocytic leukemia (CLL) disease, B cell heterogeneity and enhanced cellular proliferation play major pathogenic roles. TP53 abnormalities namely, both 17p chromosome deletion (del 17 p) and TP53mutation are considered gold standards for the clinical course of CLL and provide a better prognostic risk stratification. Objectives: This was aimed to investigate TP53 mutations in patients with CLL and to assess their impact effect on the clinical course and hematological characteristics of these patients. Patients and methods: Forty newly diagnosed CLL adult patients were selected and subjected to full history taking, clinical examination, peripheral blood & bone marrow examination, and immunophenotyping in addition to TP53 mutation by real-time PCR. Results: TP53 gene mutation was positive in 20% of CLL cases, and this mutation was significantly associated with hepatosplenomegaly, lymphadenopathy, short LDT (<12 months), CD38 expression, high-grade staging, and poor response to therapy. Conclusion: One of the most potent prognostic markers required to direct treatment decisions for CLL is the TP53 mutations, which were linked to rapid disease progression and poor outcomes.