Background & Objectives: In Egypt, most patients diagnosed as urothelial carcinoma (UC) have high grade and muscle-invasive tumors that are commonly associated with schistosomal cystitis. CD44 and p53 may represent potential targets for anticancer treatment. We aimed to assess the expression of CD44 & p53 and to determine their association in high grade, muscle-invasive tumors. Materials and Methods: Thirty four cystectomy cases with high-grade muscle-invasive UC were collected. Sections were stained for CD44 and p53 taking 10% and 20% positivity as cutoff values, respectively. Results: Median age was 60.5 years. Male/female ratio was 4:1. Fourteen cases were T2, 12 were T3, and 8 were T4. Nodal metastasis was evident in 8 cases. Conventional histology was seen in 38%, followed by squamous differentiation in 24%. Twenty patients had bilharzial cystitis. CD44 was positive in 8.8% of cases whereas p53 immunopositivity was noted in 76.5%. CD44 and p53 expression had no statistical association with stage (p=0.52 and 0.97) or bilharzial infestation (p=0.34 and 0.16). There was no significant association between CD44 expression and that of p53, p= 0.06. Conclusion: High-grade muscle-invasive Schistosomal associated urothelial carcinomas are common, but with limited CD44 and p53 co-expression.