Background: Understanding the molecular basis of prostate cancer development is essential to improve the therapeutic efficacy and to determine the clinical behavior of different cases. Genome protective mechanisms investigations is a mainstay of cancer research. Objective: To study the immunohistochemical expression of Claspin and TopBP1 in cases of prostate cancer to assess their 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 of PSA, groups of Gleason grade, higher Gleason score and advanced stage of tumor (P<0.001) for each. Positive Claspin expression was correlated with LN and distant metastasis (P<0.001). High TopBP1 score was strongly correlated with distant and LN metastasis (P=0.002, P=0.007 respectively). No association was found between both markers and age. A significant association was found between higher TopBP1 expression score & positive Claspin expression (P<0.001) and also shorter progression free survival. Upregulation of Claspin was associated with worse overall 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 may help to identify high risk patients who will benefit the most from treatment. Besides, both markers can aid in the creation of improved methods that are useful against the therapy-resistant cancer.