Purpose: Urinary bladder cancer is a very common world-wide cancer. In Egypt, there was a significant rise in the incidence of TCC in the last years. CD44 is a transmembrane glycoprotein thought to play an important role in cell-cell and cell-matrix interactions. HER-2/neu is an oncogene. Its over-expression has been associated with some different types of human cancers. The present study aimed at evaluating the prognostic value of CD44 and HER2/neu in invasive TCC of urinary bladder. Patients and Methods: This study includes 6 cases of normal bladder mucosa as a control and 40 cases of TCC (15 cases of grade 2 and 25 cases of grade 3). Cases were collected from Pathology Department, Faculty of Medicine, Benha University and Egyptian National Cancer Institute (NCI) in the period 2009 – 2011. Follow-up of the selected cases was recorded for 2 years. Immunohistochemical staining for CD44 and HER2/neu was performed in all cases and the patterns of expression were analyzed. Results: The expression of CD44 was higher in control cases than TCC and was significantly decreased in cases with poor patient prognosis (p