Colorectal cancer is a malignant tumor arising from the inner lining of the colon or rectum and is the third most common cancer and the third leading cause of cancer-related deaths in the United States. Human epidermal growth factor receptor 2 (HER2)geneoverexpressed or amplified colorectal cancer has shown treatment responses withHER2-directed therapies. We present a 78-year-old woman with metastatic colorectal cancer with aHER2 L726Imutation identified in tumor sequencing without amplification or overexpression ofHER2. She had an excellent response to fam-trastuzumab deruxtecan. Our case is the first and most noteworthy case of a patient with metastatic colorectal cancer and aHER2 L726Imutation who achieved a remarkable clinical response to fam-trastuzumab deruxtecan.