A comparative study between optical coherence tomography (OCT) and high-frequency ultrasound (HFUS) is presented to enhance imaging of bladder cancers ex vivo. A standard rat bladder cancer model in which transitional cell carcinoma (TCC) was induced by intravesical instillation of AY-27 cells was followed independently with both OCT and HFUS, and the image identifications were compared to histological confirmations. Results indicate that both OCT and HFUS were able to delineate the morphology of rat bladder [e.g., the urothelium (low backscattering/echo) and the underlying lamina propria and muscularis (high backscattering/echo]. OCT differentiated inflammatory lesions (e.g., edema, infiltrates and vasodilatation in lamina propria, hyperplasia) and TCC based on characterization of urothelial thickening and enhanced backscattering or heterogeneity (e.g., papillary features), which HFUS failed due to insufficient image resolution and contrast. On the other hand, HFUS was able to stage large T2 tumors that OCT failed due to limited imaging depth. The results suggest that multimodality cystoscopy combining OCT and HFUS may have the potential to enhance the diagnosis and staging of bladder cancers and to guide tumor resection, in which both high resolution and enhanced penetration are desirable.