OBJECTIVES Preferential use of fine-needle aspiration (FNA) versus core needle biopsy (CNB) for distinguishing benign from malignant major salivary gland tumors is highly debated. The main disadvantage of FNA is lower sensitivity, whereas arguments against CNB include use of a larger bore needle and greater risk of complications. The aim of this study is to evaluate our experience performing ultrasound-guided (UG) FNA with selective use of CNB based on preliminary cytopathology, and to determine whether our preoperative diagnostic approach is more sensitive and specific than FNA alone-and at least as sensitive and specific as CNB alone. STUDY DESIGN Retrospective review of UG needle biopsy sampling of lesions arising in or around parotid and submandibular glands. METHODS Ultrasounds of 141 needle biopsies were identified. Patient/lesion/needle biopsy characteristics, preliminary cytopathology, final pathology, imaging studies, and subsequent clinical course and treatment were documented. RESULTS Needle biopsies performed according to our protocol provided results that guided clinical decision making in 125 of 135 cases, 92.6% (95% confidence interval [CI], 86.8%-96.4%) of the time. Using 41 cases that had histologic verification, sensitivity was 100% (95% CI, 79.6%-100%), and specificity was 92.3% (95% CI, 75.9%-97.9%) for detecting malignancy. We definitively characterized 120 lesions as benign (84) or malignant (36). CONCLUSION Preoperative needle biopsy diagnoses allowed clinical management to progress 92.6% of the time. The protocol of FNA with selective use of CNB may potentially reduce patient exposure to risks associated with CNB without the tradeoff of lower sensitivity seen with FNA. LEVEL OF EVIDENCE 4. Laryngoscope, 127:2522-2527, 2017.