Background: Deficient DNA mismatch repair (MMRD) accounts for approximately 3% of metastatic colorectal cancers (mCRC). Treatment with Immune checkpoint inhibitors (ICI) in this patient population achieve an overall response rate (ORR) of up to 55%. However, to date there are no predictive biomarkers for response. Methods: A retrospective analysis of all MMRD mCRC patients that were treated with either Pembrolizumab, or Ipilimumab and Nivolumab in a large tertiary medical center between 2015-2022. The primary outcome was response to treatment and was assessed at first imaging following treatment initiation. Exposure variables included age, sex, ECOG performance status, metastatic sites (liver, peritoneum, lung, bone and brain) and CEA levels at treatment initiation. CEA below 5 mcg/l was treated as low and above as high CEA levels. Predictive biomarkers were assessed using cox hazard regression and Kaplan Meier analysis. Results: A total of 33 prospective MMRD mCRC patients were included in the study. Of them, 24 (72.7%) responded and 9 (27.3%) did not respond to immunotherapy. Median age was 70 (IQR 66-77) and 64 (IQR 51-75) for responders and non-responders respectively. Site of metastasis was an important predictor for response. Thirteen patients had liver metastasis, of them 6 (46%) responded (HR = 7.16; 95% CI = 1.47-35; p = 0.015). Five patients had single site metastasis in the liver, of them one (20%) responded (HR = 12.7; 95% CI = 2.99-53.8; p < 0.001). Fifteen patients had peritoneal metastasis, of them 13 (87%) responded to treatment (HR = 0.24; 95% CI = 0.05-1.19; p = 0.081). Median CEA at treatment initiation was 2 (IQR 1-4) in responders compared to 32 (IQR 1-70) for non-responders (HR = 5.27; 95% CI = 1.31-21.2; p = 0.019). There was no statistically significant difference between the groups in age, sex and ECOG performance status. Conclusions: Liver metastasis predict poor response to immunotherapy in MMRD mCRC patients while peritoneal metastasis and low CEA level predict response to immunotherapy.