BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized treatment of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, there is no evidence on the optimal treatment duration. We aimed to compare outcomes of different immunotherapy durations. METHODS: An international multicenter retrospective cohort study of immunotherapy-na•ve dMMR/MSI-H mCRC patients who received immunotherapy between 2014-2024. Fixed treatment duration of two years was compared to treatment duration beyond two years. Fixed treatment duration of one year was compared to treatment duration beyond one year. Subgroup analysis was performed for patients who experienced CR. Kaplan-Meier analysis and Cox proportional hazard regression model were used to analyze the effect of all exposure variables on OS. RESULTS: The study cohort included 757 dMMR/MSI-H mCRC patients treated with ICB. Median follow-up time was 46.7 months (IQR 28.5-70.3). There was no statistically significant difference in OS between patients treated for a two-year fixed-duration (n = 83) and those treated beyond two years (n = 139) in both the univariable and multivariable analysis (HR=0.65 95 %CI 0.14-3.07 p = 0.59 and HR=0.61 95 %CI 0.12-3.10 p = 0.6, respectively). The comparison between one-year fixed-duration versus continuing treatment beyond one year included 27 and 330 patients, respectively. For patients who achieved CR, discontinuing treatment after one year was not associated with a negative impact on OS (p = 0.5). CONCLUSIONS: Discontinuing immunotherapy after two years is a reasonable option for dMMR/MSI-H mCRC patients with ongoing response. Treatment discontinuation after one year may be considered for patients achieving CR. Further prospective studies are needed to define the most appropriate duration of therapy.