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Abstract: Background: Deficiencies in the DNA mismatch repair system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI). The impact of MSI on survival in metastatic colorectal cancer (mCRC) is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI in mCRC prior to the immune therapy era. Materials and Methods: A total of 75 MSI‐high (MSI‐H) mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous/synchronous) microsatellite‐stable (MSS) mCRC pts were identified from 1,268 mCRC pts who had MSI/mismatch repair test results at Mayo Clinic Rochester between January 1992 and July 2016. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized the Kaplan‐Meier method, log‐rank test, and Cox proportional hazards models. Results: The MSS group was well matched to the MSI‐H group based on age, gender, location, and chronicity of metastatic disease. MSI‐H mCRC pts had earlier disease recurrence (median time from initial diagnosis to metastatic disease diagnosis, MSI‐H group 12.9 vs. MSS group 20.9 months, p = .034). Median overall survival (OS) was 28.1 and 37.4 months for MSI‐H and MSS pts, respectively (p = .99). In total, 94.7% of MSI‐H pts and 98.7% of MSS pts had fluoropyrimidine‐based chemotherapy for metastatic disease, and there was no difference in OS between these two groups (32.3 vs. 37.4 months, p = .91). Forty‐three MSI‐H and thirty‐nine MSS pts had metastasectomy and/or ablation of metastases (p = .51) with longer median OS compared with pts without metastasectomy (MSI‐H: 82.0 vs. 13.9, p < .001; MSS: 69.9 vs. 19.7, p < .001). Age <65 years, BRAF wild type, and metastasectomy were associated with better OS in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis (p < .001). Conclusion: In mCRC, patients with MSI‐H tumors have similar, but numerically shorter, median overall survival compared with those with MSS tumors. In both groups, metastasectomy and ablation of metastatic disease should be considered to optimize OS. Implications for Practice: This study clearly demonstrated the survival benefits that aggressive metastasectomy provides in selected microsatellite instability‐high metastatic colorectal cancer patients. This could be meaningful practice‐changing information that has been long awaited. [ABSTRACT FROM AUTHOR]