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Background Treatment of mismatch repair deficient (dMMR) colorectal cancer (CRC) has been revolutionized by targeting immune checkpoints PD-1/PD-L1 and CTLA-4. The KEYNOTE-177 and CHECKMATE-8HW trials demonstrated the efficacy of immune checkpoint blockade (ICB) compared to conventional chemotherapy. Site-specific metastasis in other cancers can inhibit ICB response. We investigated how peritoneal metastasis to can affect response to ICB in dMMR CRC.Methods Medical records of patients with dMMR CRC treated with ICB at University Hospitals between 2013 and 2025 were reviewed. Demographic data including age, gender, performance status was collected. Tumor site, presence of liver, peritoneal, lung or lymph node metastasis, mutations in mismatch repair proteins and presence/absence of Lynch syndrome, and immunotherapy regimen were examined. Kaplan-Meier methodology was used to compute progression-free survival (PFS) and overall survival (OS). Survival differences were compared using log-rank test.Results From 2013-2025, 49 patients with advanced dMMR CRC were treated with ICB. Of these, 32 patients had at least one site of evaluable metastatic disease, three (10%) had Lynch syndrome. 60% of patients with metastatic disease were male, 78.1% had excellent performance status (ECOG 0/1) at beginning of treatment, 50% had progressed on at least one line of therapy, and 56.7% were stage IV at diagnosis. Patients received nivolumab (10%), pembrolizumab (70%), or ipilimumab/nivolumab combination (20%). Among 32 patients with metastasis, 16 (50%) had peritoneal metastases. Other site of metastases included liver (n=12), lymph node (n=18) and lung (n=4). Response was evaluable in 30 patients. Presence of peritoneal metastasis was associated with decreased overall response rate (57.1% vs 81.3%, p=0.07). Median PFS and OS were decreased in patients with peritoneal mets(24 months vs 29 months for PFS, 35 months vs 43 months for OS), though neither reached statistical significance. Among those patients who progressed, there was a shorter median duration of response for patients with peritoneal mets (4 months vs 16 months). Finally, of the 12 patients who progressed on immunotherapy, 10 of them showed progression in the peritoneum (83.3%).Conclusions Peritoneal metastasis is associated with a blunted response to ICB in dMMR CRC, as well as a shorter duration of response. New approaches are needed to target this niche including combination therapies.