135 Background: Regorafenib (rego) is a multikinase inhibitor approved for use in metastatic colorectal cancer (mCRC). No predictive biomarkers have been identified for rego. We conducted a real-world multi-institutional retrospective study to identify the patient and tumor characteristics associated with outcomes of rego in mCRC patients. Methods: Patients from University of Pittsburgh Medical Center and Montefiore Medical Center who received rego for mCRC were included. Patient characteristics, tumor pathology and molecular profiles, treatment history, and response to rego were collected. Primary and secondary outcomes were best objective response and progression free survival (PFS) on rego, respectively. Univariate and multivariate analyses were conducted using Fisher’s exact test, Mann-Whitney U test, Firth logistic regression and Cox proportional-hazards model. Results: 76 patients were included (median age 64, 42% females, 84% whites). Rego yielded a disease control rate of 32% (including 2 complete responses) and a median PFS of 3.6 months. Tumors with high microsatellite instability (MSI-H) had a significantly lower odds of progression of disease (POD) as best objective response (p = 0.01) and a significantly longer median PFS (p = 0.022) compared with tumors with microsatellite stability (MSS) in multivariable models (Table). 75% of MSI-H mCRC patients had not received immunotherapy (IO) prior to rego. Presence of peritoneal carcinomatosis and older age were associated with higher odds of POD (p = 0.093) and a significantly shorter PFS (p = 0.029), respectively. Compared to Whites, Black patients had a numerically higher odds of POD and shorter PFS. Sex, smoking, alcohol, sidedness of CRC, previous treatments, organs involved, and KRAS mutation were not associated with treatment response or PFS. Conclusions: Our study showed that MSI-H mCRC was associated with significantly better response to rego and PFS, even in the absence of prior IO. Other predicting factors for worse outcomes of rego included older age, and potentially peritoneal carcinomatosis and Black race. None of the mutations was found associated with treatment outcomes, with the limitation of lack of comprehensive molecular testing in many patients. Studies to further examine potential biomarkers such as MCL-1 and FBW7 mutations and correlation to clinical outcomes are ongoing. [Table: see text]