Background: PPI are widely used in pts with cancer. PPI are associated with anti-inflammatory properties and direct effects on neutrophils and monocytes that might prevent inflammation. We investigate the role of PPI on outcomes of pt receiving ICI in mUC. Methods: Medical records from pts with mUC treated with ICI from May 2013 to May 2019 using a multi-institutional database was evaluated. Use of PPI was defined: 30 days prior, during the treatment and 30 days after the last dose of ICI. ORR were assessed according to RECIST v1.1. The X² test was used to determine differences in rates. PFS and OS were estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: Overall, 115 pts received therapy with ICI. Of these pts, 20 were not included due to the absence of information about PPI. Thus, 95 pts were included for the analysis. 50 (52.6%) pts received PPI. Median age was 68 years, 79 pts (83.2%) were male, 78 pts (82.1%) had ECOG PS 0-1, 20 pts (21.1%) had liver metastasis and 36 pts (37.9%) received ICI treatment as frontline therapy. ICI prescribed were atezolizumab (58.9%), pembrolizumab (17.9%), durvalumab (12.6%), nivolumab (6.3%) and durvalumab/tremelimumab (4.2%). Pts with no PPIs use had higher ORR (CR [8.9%] +PR [14.4%]) compared to those pt who use PPIs (CR [4.4%] + PR [8.9%]) (P=0.197). Median PFS was 10.05 mo (95% CI: 3.86-16.27) for non PPI users and 3.87 mo (95% CI:1.84-5.91) for PPI users (P=0.04). Median OS was 19.71 mo (95% IC:8.93-30.49) for non PPI users and 7.9 mo (4.4-11.45) for PPI users (P=0.072). Conclusions: We have observed shorter PFS and trend toward lower OS and ORR for PPI users. The real impact of PPI should be confirmed in prospective studies.