Background: Understanding the molecular basis of prostate cancer development is essential to improve thetherapeutic efficacy and to determine the clinical behavior of different cases. Genome protective mechanismsinvestigations is a mainstay of cancer research. Objective: To study the immunohistochemical expression of Claspin and TopBP1 in cases of prostate cancer to assesstheir relationship with clinicopathological and prognostic features of the disease. Patients and Methods: Claspin and TopBP1 expression was assessed immunohistochemically in eighty-four (84)prostate cancer patients and their prognostic significance was evaluated. Results: Positive Claspin expression and high TopBP1 score were strongly correlated with high pre-treatment level ofPSA, groups of Gleason grade, higher Gleason score and advanced stage of tumor (P<0.001) for each. PositiveClaspin expression was correlated with LN and distant metastasis (P<0.001). High TopBP1 score was stronglycorrelated with distant and LN metastasis (P=0.002, P=0.007 respectively). No association was found between bothmarkers and age. A significant association was found between higher TopBP1 expression score & positive Claspinexpression (P<0.001) and also shorter progression free survival. Upregulation of Claspin was associated with worseoverall survival (p=0.045), but no association was detected among the expression of TopBP1 and overall survival(P=0.355). Conclusion: Claspin and TopBP1 expression have an important prognostic value in prostate cancer. Using them mayhelp to identify high risk patients who will benefit the most from treatment. Besides, both markers can aid in thecreation of improved methods that are useful against the therapy-resistant cancer.