The administration of kayexalate can have associated risks with different clinical impact in any patient. We must be aware of the related complications, as the histological identification of the kayexalate crystals indicates the etiology of the ischemic lesions to the clinicians and alerts them to the dangers of this therapeutic. Objective: EGFR plays an important role in colorectal cancer (CRC) progression and represents a natural target for molecular anticancer drugs. In this study we evaluated 800 consecutive CRC aimed to analyze K-Ras mutational status in relationship to: different clinical-pathological parameters, EGFR immunohistochemical (IHC) expression, response to cetuximab treatment. Method: K-Ras mutations and EGFR expression were determined by direct cycle sequencing and IHC respectively in 565 surgical specimens and 235 biopsies. IHC findings were evaluated using four different score systems. Results: The distribution of K-Ras mutations did not significantly vary between surgical or bioptic specimens or with respect to different anatomic tumor localization. In contrast, K-Ras is more frequently mutated in EGFR negative/low score tumors than in positive ones (p<0.0001). Focusing on the 419 surgical treated CRC patients, we found a higher percentage of K-Ras mutations in T4 CRC (p=0.01) and in younger patients (p=0.002). Finally, we observed that 6 % of primary CRC, concomitantly evaluated with their paired metastases, changed K-Ras mutational status during progression. Conclusion: Our data showed that tumor size, patient age and EGFR IHC expression significantly influenced K-Ras mutations. Interestingly, we observed that cetuximab treated patients, had a better clinical outcome when EGFR presented a high IHC score.