Background: In Egypt, carcinoma of the bladder is the foremost oncologic problem. It constitutes 30.3% of all cancers at the National Cancer Institute. The p63 may play a critical role in the normal development and maintenance of the human urothelium. Aim of the work: To investigate the immunohistochemical expression of p63 in normal bladder mucosa, chronic cystitis, and bladder cancer. In case of bladder cancer, we aimed to investigate the variation in its expression according to the (1) histological type, (2) grade and stage of the cancer, as well as (3) the effect of bilharziasis on its expression.Patients and Methods: A prospective, comparative study conducted on 70 patients divided into 3 groups, Group 1: 40 patients with bladder cancer, Group2: 20 patients with cystitis (bilharzial and non-bilharzial), and Group 3: 10 patients with apparently normal urothelium as a control. Biopsies were taken from the tumors and bladders either by a resectoscope or a cold-cup forceps. In case of patients subjected for radical cystectomy, the biopsies were taken from the bladder specimen after the operation. All retrieved tissue specimens were examined for the expression of p63 by immunohistochemical techniques.Results: The mean age + for the malignant, cystitis, and control groups was 60.52 + 9.9, 50.5 + 11.7, 45.2 + 9.5 respectively. There was a statistically significant decrease in the immunoreactivity in the malignancy group compared to the other groups (p<0.05). Also, there was a significant decrease in the immunoreactivity in association with the advancement in the tumor stage and grade was present (p<0.01). In case of Squamous cell tumors, there was a decrease in p63 immunoreactivity rather than in the transitional cell tumors (p<0.01). Regarding the impact of bilharziasis on p63 expression, there was a tendency for the statistically significant decrease in p63 immunoreactivity in bilharzial cystitis patients (p<0.01), but in the malignant group, we noticed that bilharziasis did not affect the pattern of p63 expression.Conclusion: Our data suggest that p63; at the time moment; could be a helpful biomarker and adjunct in predicting the tumor biological behavior and progression but we recommend further studies to elucidate exactly its role as a prognostic indicator especially for non-invasive tumors and its utility as a tumor marker.