Background: Homologous recombination repair (HR) is the most accurate repair pathway for double-strand breaks and replication fork disruption that is capable of faithfully restoring the original nucleotide sequence of the broken DNA. The deficiency of this mechanism is a frequent event in tumorigenesis. Therapies that exploit defects in HR have been explored essentially in breast, ovarian, pancreatic, and prostate cancers, but poorly in colorectal cancers (CRC), although CRC ranks second in mortality worldwide. Methods: Tumor specimens and matched healthy tissues from 63 patients with CRC were assessed for gene expression of key HR components and mismatch repair (MMR) status, which correlated with clinicopathological features, progression-free survival, and overall survival (OS). Results: Enhanced expression of MRE11 homolog (MRE11A), the gene encoding a key molecular actor for resection, is significantly overexpressed in CRC, is associated with the occurrence of primary tumors, particularly T3-T4, and is found in more than 90% of the right-side of CRC, the location with the worst prognosis. Importantly, we also found that highMRE11Atranscript abundance is associated with 16.7 months shorter OS and a 3.5 higher risk of death. Conclusion: Monitoring of MRE11 expression could be used both as a predictor of outcome and as a marker to select CRC patients for treatments thus far adapted for HR-deficient cancers.