OBJECTIVES: To perform a cost-effectiveness analysis based on markers of response/resistance including biological therapies available in Spain for metastasic colorectal cancer (mCRC). METHODS: Incremental cost-effectiveness ratio (ICER) per life-year gained (LYG) and progression-free year gained were calculated based on predictive markers for mCRC. Efficacy data include randomized trials (RT) that guided on-label uses of bevacizumab and cetuximab. Control arms from these trials were used as reference scenario. Markers of clinical benefit (biological & radiological) were included. Toxicity as predictor of efficacy was excluded for any therapy. Prices for drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs.  For 1st line, median duration of therapy reported by RT was used to calculate the final budget. 70kg and 1.7 m were used as reference for patients dose calculations. If accessible, HR for PFS and OS were used instead of medians. RESULTS: K-Ras status and early response measured by computed tomography at 8 weeks were used as predictors of resistance and increased efficacy for cetuximab-based combinations. We have not identified any predictor marker for other drugs from RT. In this regard, FOLFIRI+cetuximab combination obtained an ICER below the widely-proposed Spanish threshold of 30,000 € per LYG if patients harbored wild type (wt) K-Ras tumors and evidenced an objective response at 8 weeks. Other ICERs for different schedules were too distant from this limit. Multivariate analysis confirmed the robustness of results. CONCLUSIONS: First-line FOLFIRI+cetuximab therapy for wt K-Ras patients that get an objective response measured by CT at 8 weeks is the only cost- effective therapy option for mCRC below usual health economics thresholds for Spain. Our results are critical to design cost-effectiveness based clinical guidelines for mCRC that will contribute to financial sustainability of public health system in Spain.