Background: Patients with high-risk MIBC have a poor prognosis. Radical cystectomy remains the standard treatment. Yet despite substantial improvements in surgical techniques, mortality from metastatic recurrence remains high. A large number of MIBC patients are ineligible for cisplatin-based chemotherapy or have persistent muscle-invasive disease despite neoadjuvant chemotherapy (NAC). Pembrolizumab, a PD-1 inhibitor, has demonstrated significant activity and is FDA-approved for patients with advanced/chemotherapy-refractory metastatic urothelial carcinoma. We hypothesize that pembrolizumab given post-cystectomy will improve overall survival (OS) and disease-free survival (DFS) in patients with high-risk MIBC. Methods: Patients must have histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract, have received NAC and have ≥ pT2 and/or pN+ at surgery or be cisplatin-ineligible and have ≥ pT3 and/or pN+ at surgery or have declined adjuvant cisplatin-based therapy and have ≥ pT3 and/or pN+ at surgery. Surgery could be radical cystectomy, nephrectomy, or ureterectomy. Patients are stratified by pathologic stage, central PD-L1 status, and prior NAC. Patients are randomized to receive pembrolizumab 240 mg every 3 weeks for 1 year, or observation. The dual primary objectives are to determine DFS and OS. Secondary objectives are to determine DFS and OS in PD-L1-positive and -negative patients and assess safety. Correlative objectives are to determine whether 12 immune gene signatures, tumor molecular subtypes, diversity of T-cell receptor (TCR) clonotypes, persistence of TCR clonotypes, tumor and neoantigen burden, HLA subtypes, and plasma HGF and VEGF levels with IL-10 and IL-17 are associated with OS and DFS. Quality of Life Correlative objectives are to compare health-related quality of life as assessed by the EORTC QLQ-C30. Clinical trial information: NCT03244384