Background: For patients with refractory metastatic colorectal cancer (mCRC), both trifluridine/tipiracil (TAS-102) and regorafenib have received approval for use in the United States. The approvals of these agents were based on modest improvements in overall survival (OS) when compared to best supportive care plus a placebo in the RECOURSE and CORRECT trials, respectively. However, TAS-102 and regorafenib have never been directly compared in a prospective clinical trial. This study utilized a large real-world database to compare clinical outcomes with use of these agents. Methods: The nationwide de-identified Flatiron Health EHR-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least two lines of guideline recommended therapy for advanced disease followed by treatment with TAS-102 and/or regorafenib in the third line or greater were included for analysis. Patients who did not have a visit or medication order within 90 days of metastatic diagnosis were excluded to ensure patients were engaged with care at the data-providing institution. Kaplan-Meier and propensity score weighted models were used to compare survival outcomes between groups. Results: The records of 22,078 patients with mCRC were reviewed. Of the 4,407 patients that received at least two lines of standard therapy, 2,072 subsequently received regorafenib and/or TAS-102. Of these, 813 (39.2%) received TAS-102 alone, 275 (13.3%) TAS-102 followed by regorafenib, 736 (35.5%) regorafenib alone, and 248 (12.0%) regorafenib followed by TAS-102. Median OS for patients treated with TAS-102 alone or prior to receiving regorafenib was 6.66 months (95% CI 6.16-7.18) compared to 6.30 months (95% CI 5.80-6.79) for those treated with regorafenib alone or prior to receiving TAS-102 (p = 0.36). A propensity score weighted analysis controlling for age, race, stage at initial diagnosis, performance status at start of therapy, MSI/MMR status, RAS/RAF status, and line in which TAS-102 or regorafenib was received did not demonstrate a significant difference in survival between groups (HR 0.99, 95% CI: 0.90 -1.09, p = 0.82). A subgroup analysis did not identify any significant differences in outcomes stratified by age, performance status, MSI status, or RAS/RAF status. Conclusions: This analysis of real-world data did not identify a significant difference in survival outcomes in mCRC patients who were treated with TAS-102 or regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. This data should be considered when discussing the risks and benefits of TAS-102 and regorafenib with mCRC patients who are eligible for third line or greater treatment.