Background: Markers of systemic inflammation including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (LMR) are prognostic in patients with metastatic colorectal cancer receiving systemic chemotherapy. The presence of liver metastases has also been hypothesized to modulate response to immunotherapy. In this study, we assess the prognostic role of these markers in patients with microsatellite high (MSI-H)/deficient mismatch repair (dMMR) tumors receiving immunotherapy for metastatic or unresectable colorectal cancer (CRC). Methods: This was a single-institution retrospective analysis of patients with dMMR/MSI-H CRC who received anti-PD-(L)1 and/or anti-CTLA-4 therapy for metastatic or unresectable disease at between 2015 and 2021 (n = 59). NLR, PLR, and LMR were calculated based on the complete blood count obtained within 1 week prior to treatment. Patient and tumor characteristics were obtained from the clinical record. Patient characteristics were compared using Fisher’s exact test and Mann-Whitney U where appropriate. Progression free survival (PFS) and overall survival (OS) were the primary endpoints and log-rank test was used for comparison of survival distribution among groups. Results: 59 patients with metastatic dMMR/MSI-H CRC were identified. Median age was 60, 53% (n = 31) had right-sided tumors, 35% (n = 35) of patients with testing available had RAS-mutated tumors, and 37% (n = 22) received prior chemotherapy. Most common sites of metastatic disease were peritoneum (n = 23, 39%) and liver (n = 17, 29%). Patients were divided into NLR-High (NLR ≥ 3, n = 20) and NLR-Low (NLR < 3, n = 39), and both groups had similar baseline characteristics. The rate of progressive disease as best response was not different in NLR-Low versus NLR-High (15% vs 30%, p = 0.3). At a median follow-up of 32 months, neither median PFS nor median OS were reached. 74% (n = 29) remained progression free at 1 year in the NLR-Low group versus 60% (n = 12) in NLR-High group which was not statistically significant (p = 0.37); 90% (n = 35) remained alive at 2 years in the NLR-low versus 80% (n = 16) in the NLR-High group (p = 0.4). Similarly, using a cut-off of 150 and 3 for PLR and LMR respectively, there was no significant difference between PFS at 1 year in the PLR-Low (n = 32) vs PLR-High (n = 27) (66% vs 74%, p = 0.58) and LMR-Low (n = 35) vs LMR-High (n = 24) (60% vs 83%, p = 0.084) groups. The presence of liver metastasis or the presence of a RAS mutation did not influence PFS at 1 year (p = 0.35 and p = 1.00, respectively). Conclusions: Markers of systemic inflammation may have a limited prognostic role for patients with dMMR/MSI-H CRC receiving immunotherapy.