Salivary ductal carcinoma (SDC) is a high-grade malignancy, and molecular studies show frequent overexpression of human epidermal growth factor receptor 2 (HER2). We reviewed our experience with molecular-targeted therapy using trastuzumab for patients with HER2-positive SDC. The records of all patients treated with trastuzumab for HER2-tested SDC at The University of Texas MD Anderson Cancer Center between 1997 and 2011 were reviewed. Thirteen patients with SDC overexpressing HER2 were treated with trastuzumab as a single agent or in combination with chemotherapy. Ten of these had 3+ immunohistochemistry or HER2 gene amplification by fluorescence in situ hybridization. Patients underwent therapy in the surgical adjuvant setting (n=2), as a component of combined therapy for advanced disease (n=8), or as single therapy near end of life (n=3). Treatment efficacy via radiographic review for response could not be assessed. Trastuzumab should undergo prospective therapeutic clinical trials, in SDC which will likely require international cooperation.