Overexpression of HER2 protein and amplification of the ERBB2 gene has been observed in various adenocarcinomas, providing a therapeutic target that can be used to extend the survival of a select cohort of patients. Anti-HER2 therapy has been successfully applied to gastric and colorectal cancers, but its use and potential benefit in small intestinal carcinomas is not well characterized. We applied anti-HER2 therapy to an ERBB2-amplified advanced duodenal adenocarcinoma, adding trastuzumab to FOLFOX in the neoadjuvant setting. A 61-year-old woman with an advanced duodenal cancer harboring an ERBB2 amplification received preoperative trastuzumab and FOLFOX. Restaging revealed significant tumor downstaging with no metastasis. After multidisciplinary assessment, she underwent pancreaticoduodenectomy. Final pathologic analysis revealed no residual invasive adenocarcinoma, consistent with a complete neoadjuvant treatment response. This case report emphasizes the need for further molecular characterization of small bowel cancers; genetic alterations may provide therapeutic targets to improve the prognosis of these rare and aggressive malignancies.