Background: Colorectal brain metastases (cBM) confer a devastating prognosis with survival of less than 13 months. Identifying genomic signatures to predict and guide treatment for these patients would be a valuable adjunct. This study evaluated genomic and clinicopathological features specific to cBM. Methods: cBM patients from the MSK-MET cohort were evaluated in comparison to other colorectal cancer patients with extracranial metastases (cOM). Clinicopathologic features and genomic alterations were analyzed with MSK-IMPACT, a targeted DNA sequencing panel for solid tumors and matched blood specimens. We considered mutations, copy number alterations, and fusions. Analyses of genomic features were restricted to microsatellite stable (MSS) patients. q-values were computed using Benjamini-Hochberg correction to account for multiple hypothesis testing. Patient record review identified patients with sequenced matched samples from the primary colorectal tumor and the brain metastases, which were then examined for loss and gain of assessed genetic alterations. Results: Of 130 patients with cBM identified from the cohort, 20 samples were from brain metastases, 52 from the primary CRC, and 58 from other metastatic sites. Average time to diagnosis of cBM was 3.5 years after primary colorectal cancer diagnosis and average time to death was 10 months after cBM diagnosis. Compared to the 3,383 cOM patients, cBM patients had significantly higher rates of both MSS CRC primaries (p<0.001, 122/130 cBM were MSS vs. 3,038/3,382 cOM) and primaries that originated in the rectum (p<0.002, with 38/130 cBM primaries from the rectum vs. 695/3,382 cOM rectal primaries). Somatic alterations in the KRAS, BRCA2, CDK8 and ERCC5 genes were significantly more frequent in patients with cBM compared to cOM patients (all p<0.001) (Table 1). Of the 9 patients who had matched primary and metastatic brain tissue sequenced, KRAS alterations were shared between the primary and brain metastasis in 2/9, ERBB3 and ERCC5 in 2/9, p53 in 6/9, and APC in 6/9 patients. In addition, newly acquired private alterations found only in the brain metastasis samples of matched patients included PIK3RI, ARID5B, NOTCH4, CYLD and SMAD4. Conclusions: We identify new genomic and clinical factors in cBM patients, including somatic alterations in potentially clinically actionable targets. To further explore potential clinical utility, these findings require validation in an independent cBM clinicogenomic dataset.