Background: There is an unmet need for systemic treatment options in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based neoadjuvant chemotherapy. The PURE-01 trial has also demonstrated preliminary efficacy when pembrolizumab is used in the neoadjuvant setting. We aimed to compare pathologic response and survival outcomes in cisplatin-ineligible patients receiving neoadjuvant pembrolizumab (NAP) vs. immediate radical cystectomy (IRC). Methods: Cisplatin-ineligible MIBC patients were identified from the PURE-01 trial and compared against cisplatin-ineligible MIBC patients treated with immediate radical cystectomy (IRC). Overall survival was analyzed using Kaplan-Meier and Cox Proportional Hazards Modelling. IRC patients were matched via nearest neighbor propensity technique to cisplatin-ineligible patients from PURE-01 by ECOG status, GFR, age, sex, and clinical T stage. Results: Thirty-nine cisplatin-ineligible patients treated with NAP were identified from PURE-01, and compared against 313 cisplatin-ineligible patients undergoing IRC (Figure 1A). OS was prolonged in the NAP patients, with median survival of 19 months in the IRC vs. not reached (NR) in the NAP group (p=<0.01). Following nearest neighbor matching, 39 patients were identified from the IRC cohort, with comparable baseline clinicopathologic variables as listed in the table. Patients receiving NAP experienced a higher complete response rate on final pathology (pT0: 33% vs. 13%, p=0.03). Median OS was prolonged in the propensity score matched analysis (NAP NR vs. IRC 21.0mo, p<0.01), specifically at 12mo (89% vs. 57%), 24mo (64% vs. 28%), and 36 months after surgery (33% vs. 13% ) (p<0.01). Compared to NAP, cisplatin-ineligible patients undergoing IRC experienced worse OS, with a Hazard Ratio of 2.0 (95% CI 1.1 - 3.89). Conclusions: Cisplatin-ineligible patients receiving NAP for muscle invasive bladder cancer had a higher rate of downstaging and a survival advantage over patients who underwent IRC. Although this study suggests promising systemic options for cisplatin-ineligible patients in the neoadjuvant setting, results of ongoing prospective randomized trials will help validate these findings and provide therapeutic options to cisplatin-ineligible patients.