Background: Treatment guidelines for second-line therapy of metastatic colorectal cancer (mCRC) suggest that addition of an anti-angiogenesis inhibitor to standard chemotherapy will prolong survival. Bevacizumab and aflibercept are two inhibitors that have increased survival in randomized clinical trials, but their cost-effectiveness is unclear. This study uses clinical trial data to compare the addition of aflibercept versus bevacizumab to a chemotherapy regimen in terms of incremental cost-effectiveness ratios (ICERs) in cost per month gained and treatment-related toxicities. Methods: A Markov model was used to simulate survival, toxicities, and costs for each treatment arm. Survival and adverse event probabilities were derived from published clinical trial data, and costs were estimated from the literature and the 2013 Veterans Affairs Federal Supply Schedule. Results: Aflibercept dominates bevacizumab by increasing survival by 1.06 months, while saving $3,526 in total treatment and adverse event costs combined (Table). When evaluating only adverse event-associated costs, the ICER between aflibercept and bevacizumab is $3,675 per month gained. One-way sensitivity analysis of the total cost ICER shows that aflibercept cost-savings are robust to almost all parameters varied, while similar analysis of the adverse event ICER suggests that aflibercept-associated toxicities would cost less than bevacizumab-associated toxicities in the case of a 20% decrease or increase in aflibercept or bevacizumab toxicity costs, respectively. Conclusions: Aflibercept plus chemotherapy is cost saving overall and improves survival compared with bevacizumab plus chemotherapy but results in more adverse events and associated costs. Practitioners treating mCRC patients should weigh survival outcomes against potential increased toxicity between different treatments, especially when evaluating limited survival gains.