Background: Next-generation sequencing (NGS) based molecular profiling technologies have revealed several oncogenic fusion genes that are actionable with small molecule inhibitors leading to practice change, particularly in lung cancer. The molecular and clinical characteristics of these gene fusions are not well defined in colorectal cancer patients (CRC). In this study, we aimed to define clinical and molecular characteristics of fusion genes in patients with CRC who underwent molecular profiling. Methods: Molecular characteristics of tissue confirmed 917 CRC patients were retrieved from the Moffit Cancer Center Clinical Genomics Action Committee database. Patients’ demographic and clinicopathological features and treatment history were collected from the database. All fusion genes were shown by hybridization-based NGS computational algorithms that determined cancer‐related genes, including single‐nucleotide variations, indels, microsatellite instability (MSI) status. Results: Among a total of 917 patients, 24 patients with CRC (2.6%) were found to have at least one fusion gene with a total number of 26 pathogenic fusions. The gene fusions are shown in Table. The most common, potentially targetable, fusion genes in our cohort were (1) RET fusions 0.5% (5/917), (2) ALK fusions 0.4% (4/917), (3) ROS1 fusions 0.2% (2/917), (4) NTRK1 fusion 0.1% (1/917), (5) NRG1 fusion 0.1% (1/917). Fusion genes were more common in MSI-H CRC (N = 27), and 3 (11.1%) patients with MSI-H CRC were found to have fusion genes [(RET (2) and NTRK(1)]. Fusion genes were present in both RAS wild-type (54%; 13/24) and RAS mutant (46%; 11/24) tumors. Most patients were older than 50 years (75%, 18/24) and had left-sided tumor (61.1%) tumor. Conclusions: Fusion genes are rare events in CRC. While fusion genes seem to be more prevalent in MSI-H CRC, RAS status does not correlate with the frequency of fusion genes. Actionable RET and ALK/ROS gene fusion are more common than NTRK fusion genes in this cohort of CRC patients.