Background In thyroid nodule fine-needle aspiration (FNA) cytology, the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category has a 5-15% malignancy risk that increases to 85-99% when mutation testing for BRAF, RAS, RET/PTC, or PAX8/PPARγ is positive. However, negative testing does not exclude malignancy. The study objective was to identify clinical and imaging features that predict cancer in mutation-negative AUS/FLUS thyroid nodules. Methods All patients were reviewed (April 2007 to April 2009) who had AUS/FLUS cytology, negative prospective molecular testing of FNA, and histopathology. Results Of the 230 nodules, 12 (5.2%) were malignant in 11 of 190 patients, and known clinical risk factors for thyroid cancer did not predict malignancy. On preoperative imaging, ≥1 suspicious ultrasound feature was identified in 33% of nodules and occurred regardless of histology (P =.23). Malignant mutation-negative AUS/FLUS nodules were larger than benign nodules (mean maximum diameter, 33.6 vs 24.0 mm; P =.007). On multivariate analysis, nodule size remained an independent predictor of malignancy (odds ratio, 1.043; P =.018). We observed no malignancies in 88 mutation-negative AUS/FLUS nodules <18.5 mm. Conclusion Size is an independent predictor of malignancy in mutation-negative AUS/FLUS nodules and the risk increased 4.3% with every millimeter increase in nodule size. Selected patients with small, mutation-negative AUS/FLUS thyroid nodules may be managed with ultrasound surveillance in lieu of thyroidectomy.