Background: KRAS is down-regulated by Let-7 microRNA isoforms and this effect may be clinically relevant to patients harboring KRAS mutations. We quantified the Let-7a isoform in KRAS-mutated colorectal carcinomas of patients who received salvage irinotecan/cetuximab. The Let-7a levels were characterized and studied for association with survival outcomes. Methods: The study population was retrospectively identified among metastatic colorectal cancer (mCRC) patients who underwent third-line cetuximab/irinotecan before 2008. At that time epidermal growth factor receptor (EGFR) expression only was required for adopting the anti-EGFR therapy. In 59 eligible patients harboring KRAS mutations, tumoral Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS). An exploratory sub-group analysis was performed to detect the single nucleotide polymorphism (SNP) rs61764370 G/A (LCS6) in the region that experimentally impairs the Let-7 binding to the KRAS mRNA. Results: Among clinico-pathologic features, high Let-7a levels were associated with grade 2-3 skin toxicity (p=0.002). Differences in Let-7a levels were not found between paired tumor and non-tumor samples in 39 cases (66%) with availability of both tissues. Increased Let-7a levels were significantly associated with improved survival (multivariate Hazard Ratio=0.88; 95%CI=0.79-0.98; p=0.02). In the exploratory analysis the variant G allele of the LCS6 occurred in 14 patients and among the 45 A/A LCS6 homozygous patients, there was a significantly favorable association between high Let-7a levels and both OS and PFS. Conclusions: Replication of these data is warranted. In patients with KRAS mutation, Let-7 analysis may serve for identifying subgroups who may still gain some benefit from EGFR inhibition and it may open new perspectives for alternative treatment strategies.