Background: Microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients who have failed chemotherapy have shown response to checkpoint blockade. We investigate optimal third-line treatment in MSI-H mCRC with regard to overall survival, quality of life years gained (QALYs), and cost-effectiveness. Methods: A Markov Model was created for a base case of a 57 year old man with MSI-H mCRC refractory to two lines of chemotherapy. Treatments compared were nivolumab, nivolumab with ipilimumab, and trifluridine/tipiracil. Patients could remain stable, progress to fourth-line chemotherapy or palliative care, experience drug toxicity, die from age/sex mortality, or die from cancer over their simulated lifetimes. Transitions between health states were based on the CheckMate 142 and RECOURSE trials. Outcomes were survival or unadjusted life years, QALYs, and incremental cost-effectiveness ratios (ICERs). The willingness to pay threshold was $100,000/QALY. Results: Nivolumab with ipilimumab was the most effective strategy as it yielded more unadjusted life-years (4.24) and QALYs (2.53) compared to nivolumab (3.95 LY, 2.33 QALYs) and trifluridine/tipiracil (0.74 LY, 0.07 QALYs). However, nivolumab with ipilimumab was not cost-effective compared to nivolumab and neither treatment strategy was cost-effective compared to trifluridine/tipiracil. Sensitivity analysis found nivolumab monotherapy could be cost-effective with decrease in drug cost to $2000/dose. Conclusions: Our modeling analysis finds that both single and dual checkpoint blockade yield significantly increased overall survival and QALYs for MSI-H mCRC compared to third-line chemotherapy, but were not cost-effective because of nivolumab cost. Decreases in drug pricing and/or duration of maintenance nivolumab could make nivolumab monotherapy cost-effective.