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BACKGROUND: Loss of MHC I expression is a tumoral escape mechanism, part of the process of immunoediting. MHC expression patterns and their prognostic and predictive value have not been studied in urothelial carcinoma of the bladder (UC) so far. OBJECTIVE: To correlate the expression of MHC I and MHC II with prognosis after curative treatment, response to chemotherapy and checkpoint inhibition. PATIENTS AND METHODS: We analyzed different patient cohorts for their expression of MHC I(HLA-A/B/C) and II (HLA-DR/DP/DQ) and examined potential correlations with prognosis and response to cisplatin-based chemotherapy or PD-1/PD-L1 directed immunotherapy. RESULTS AND LIMITATIONS: Overall, MHC expression was analyzed in 246 patients, and complete MHC I loss was seen in 29.7% of patients. In 35% of patients aberrant tumoral expression of MHC II was observed. In a homogeneous cohort of 149 patients with cystectomy with curative intent there were no significant differences in survival between the MHC expression groups. MHC I+ and MHC II+ patients had higher infiltration densities with CD8+ T effector cells. An analysis of 77 additional patients (cohort II) with neoadjuvant chemotherapy revealed no associations of MHC status with response defined as <  pT2 pN0 in the cystectomy specimen. Lastly, we analyzed 26 patients with metastatic disease treated with PD-1/PD-L1 directed immunotherapy (cohort III, best response: 11 PD, 5 SD, 10 OR) and observed responses exclusively in MHC I+ patients (10/19 patients, 52.6). All four MHC I+ /MHC II+ /PD-L1+ patients had a progression-free interval of at least 12 months. CONCLUSIONS: Tumoral MHC I expression is frequently lost in UC. We found no association with prognosis or response to cisplatin-based chemotherapy but response to checkpoint inhibitors was limited to MHC I+ patients.