Background: Prostatic adenocarcinoma and urothelial carcinoma of the urinary bladder are common cancers in men. High grade forms of these tumors may present ambiguous morphologic features that make distinguishing invasive high-grade urothelial carcinoma (UC) from high-grade prostatic adenocarcinoma difficult. The distinction between the two tumors has significant staging and therapeutic implications. Hence, an accurate diagnosis is essential. Aim: To compare the expression of GATA3 and p63 in urothelial carcinomas and adenocarcinomas of prostate. Materials and Methods: Immunohistochemistry (IHC) for GATA binding protein 3 (GATA3) and p63 was performed on a tissue sections of 30 cases of invasive high-grade UC and of 30 high-grade prostatic adenocarcinomas, Results: GATA3 and p63 were positive in 25 (83.3%) and in 27 (90%) of high-grade UC, respectively. All GATA3 positive staining was diffuse, from which 22 (88%) cases demonstrated moderate-strong staining, and 3 (12%) cases demonstrated weak staining. Of the 5 cases that failed to express GATA3, 3 were positive for p63, while 2 cases were negative for both 2 markers. None of the prostatic adenocarcinomas expressed either GATA3 or p63. Conclusion: GATA3 and p63 IHC are sensitive markers for UC and can be used to distinguish prostatic adenocarcinomas from urothelial carcinomas in difficult cases. They are also highly specific in excluding high-grade prostatic carcinoma.