Abstract Introduction/Objective High-grade urothelial carcinoma (HGUC) shows marked morphologic plasticity with many recognized histologic subtypes that may coexist within the same tumor. These pose a diagnostic challenge and should be distinguished from collision tumors, defined by the coexistence of morphologically and genotypically distinct tumors at the same anatomic site. Herein, we present the first case of HGUC with malignant prostatic differentiation mimicking a collision tumor in a bladder diverticulum. Methods/Case Report 68 yo male presented with gross hematuria and was found to have a 2.2 cm tumor in a posterior bladder diverticulum. Initial transurethral resection (TUR) suggested HGUC, while re-TUR showed prostatic adenocarcinoma. Subsequent diverticulectomy specimen revealed two morphologically and immunohistochemically distinct tumor components: 1) a papillary component associated with urothelial carcinoma in situ, positive for CK903 and GATA3, and compatible with HGUC of the bladder, and 2) a distinct and intimately admixed malignant glandular component, which was GATA3 negative, but positive for markers of prostatic differentiation such as NKX3.1, PSA and PSAP and displayed prostatic duct adenocarcinoma features. Accurate diagnosis of this lesion is crucial, and a few possibilities exist: 1) a collision process between urothelial carcinoma of the bladder and a previously undiagnosed duct carcinoma of the prostate metastatic to the bladder diverticulum; 2) prostate cancer arising from an ectopic prostatic epithelium located in the bladder submucosa; 3) HGUC with malignant divergent prostatic differentiation. To this end, papillary and glandular tumor components were macrodissected and subjected to targeted massively parallel sequencing. Disease-associated variants in EGFR, DDR2, KMT2D, and RB1 were identified and were identical and shared among the two histologically distinct components. These findings suggest that the two components are part of the same neoplastic process and represent a urothelial carcinoma with divergent prostatic differentiation. Of note, the patient’s initial and subsequent PSA levels were within normal limits, and magnetic resonance imaging of the prostate was unremarkable. Results (if a Case Study enter NA) NA Conclusion Awareness of divergent differentiation in urothelial carcinomas has important diagnostic, prognostic and therapeutic implications and can be resolved with the use of ancillary and molecular studies.