OBJECTIVES: ESMO Clinical Guidelines for metastatic Colorectal Cancer treatment (mCRC) were updated in 2014. The objective is to assess the clinical (measured by overall survival, OS) and economic implications of its recommendations from the Spanish national healthcare system view. METHODS: A calculator was designed in order to analyze and compare the clinical and economic outcomes of the scenarios presented in the guideline. A systematic review was performed on all the information about the dosage and frequency of administration found in the summary of product characteristics of the different products included in the treatment algorithms. Current pricing and reimbursement conditions in Spain of every biologic and chemotherapy drug considered in the guidelines were checked. RESULTS: The first scenario, which places bevacizumab as first and second line treatment (concept of continuum of care) and anti-EGFR antibody as third line out of the four lines considered, yields an estimated OS of 20.2 months and total cost of 52,000€ per patient. The second scenario, which places bevacizumab as first line treatment and includes anti-EGFR antibody as second line in order to rescue the patients who have failed in the previous treatment, results in an estimated OS of 25.0 months and total cost of 50,000€ per patient. Finally, the third scenario places anti-EGFR antibody available for WT RAS patients as first line treatment and bevacizumab as second line out of three lines. When cetuximab is chosen as the anti-EGFR first line therapy, estimated OS is 33.1 months and the total cost does not exceed 40,000€. CONCLUSIONS: This analysis not only demonstrates that the use of more agents does not always assure a better clinical result, but that the use of cetuximab as first line treatment in WT RAS mCRC patients stands as the most efficient and cost-effective alternative maximizing OS.