This study aims to investigate Desmocollin 2 (DSC-2) expression in TCC and SCC, and its role in the differentiation between TCC and SCC. Materials and Methods: DSC-2 immunostaining was studied in 90 specimens of bladder carcinomas using avidin-biotin peroxidase method. Results: DSC-2 was strongly expressed in 11/31(35.5%) of invasive TCC. DSC-2 was detected in all TCC with squamous differentiation. DSC-2 expression was weak in 3/35 (8.6%), moderate in 13/35 (37.1%), and strong in 19/35 (54.3%) of cases of SCC. In cases of undifferentiated carcinoma of the urinary bladder DSC-2 expression was weak in 2/13 (15.3%), strong in 5/13 (38.5%), and negative in 6/13 (46.2%). There was significant difference in DSC-2 expression correlating SCC to TCC with foci of squamous differentiation to pure TCC (P< 0.000). DSC-2 offers high sensitivity of (100%) and high specificity (95.2%) for the detection of squamous differentiation in TCC. Conclusion: Being expressed in all SCC, sites of squamous differentiation in TCC, DSC-2 could be a useful marker for differentiation between poorly differentiated SCC and poorly differentiated TCC