OBJECTIVES: To estimate the incremental cost per life-year gained (LYG) of aflibercept in combination with FOLFIRI as second-line treatment in metastatic colorectal cancer (mCRC) in Best Efficacy Subgroup (BES) patients previously treated with oxaliplatino compared to FOLFIRI. METHODS: A post-hoc analysis of the VELOUR clinical trial revealed an improvement of aflibercept efficacy in a specific subgroup. BES was composed by patients with performance status (PS) 0 with any number of metastatic sites or PS 1 with <2 metastatic sites, exclusive of adjuvant fast relapsers. A Markov model with 3 health states (stable disease, progression and death) was used to estimate lifetime costs and outcomes (2-weeks cycle duration). Transition from stable disease to progression implied the interruption of second-line treatment and administration of a third-line chemotherapy (72%) or best supportive care (28%). According to the National Health System (NHS) perspective only direct costs were considered. Cost estimation (€, 2015) included pharmaceutical and administration cost, adverse event management and hospital and medical visits consumption. Ex-factory price with mandatory deduction was applied for drug cost estimation. Costs and outcomes were 3% annually discounted. Sensitivity analyses (SA) were performed.  RESULTS: Administration of aflibercept + FOLFIRI as second-line treatment on BES was more effective than FOLFIRI, yielding 1.92 LYG (23 life-months gained) compared to 1.55 LYG (18.6 months). Aflibercept + FOLFIRI accounted a total cost of €40,449, compared to €25,698 estimated for FOLFIRI. The incremental cost-effectiveness analysis provided a €33,373/LYG ratio for aflibercept in combination with FOLFIRI versus FOLFIRI for BES. SA results confirmed the model robustness. CONCLUSIONS: According to a post-hoc analysis, aflibercept in combination with FOLFIRI could increase overall survival versus FOLFIRI on BES. Aflibercept + FOLFIRI could be an efficient strategy for second-line treatment in specific mCRC patients for the Spanish NHS.