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Background: The prognostic implication of wild‐type APC (APC‐WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined. Materials and Methods: APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC). Results: In comparison with the APC‐mutant (APC‐MT) population (n = 255), APC‐WT patients (n = 86) tended to be younger (59% of age < 40 vs. 26% of age > 50), right‐sided (41.7% vs. 27%), BRAFV600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over‐represented in the APC‐WT versus APC‐MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC‐WT patients had a worse overall survival (OS) than APC‐MT patients (22.6 vs. 45.6 months, p <.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC‐WT was predictive of poor survival (APC‐MT vs. APC‐WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44–0.86, p =.0037). The prognostic implication of APC‐WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC‐MT vs. APC‐WT, HR, 0.63, 95% CI, 0.49–0.81, p <.0001). Conclusion: APC‐WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC‐MT mCRC tumors, APC‐WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC‐WT patients. Implications for Practice: Patients with microsatellite stable metastatic colorectal cancer with wild‐type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients. Despite advancements in therapy, colorectal cancer is still a leading cause of cancer‐related death in the U.S. This article evaluates the prognostic value of wild‐type APC in patients with microsatellite stable colorectal cancer. [ABSTRACT FROM AUTHOR]