Objective: The aim of this study was to ascertain the relationship between Bethesda category and molecular mutation of thyroid nodules in patients undergoing thyroidectomy. Design: A retrospective cohort of patients who underwent thyroidectomy following needle biopsy and molecular profile testing was performed. Setting: Two tertiary care academic hospitals. Participants: Consecutive patients with a dominant thyroid nodule who underwent both USFNA and molecular profile testing followed by thyroidectomy were included in the study. Main Outcome and Measures: The main outcome was postoperative diagnosis of thyroid cancer and aggressivity of disease based on histopathological variants, nodal metastasis or extra-thyroidal extension. Associations between Bethesda category, molecular mutation and postoperative pathology was assessed using descriptive analysis and Chi-square testing. Results: 451 patients were included. 95.9% (93/97) of patients with a BRAFV600E mutation had a Bethesda category V or VI (P<0.001), and all had confirmed thyroid cancer on postoperative pathology. Those with H, K or N RAS or EIF1AX mutations, gene expression profiling (GEP) or copy number alterations showed an association with Bethesda categories III and IV (P≤0.01). Those with no identified molecular mutation had a lower incidence of aggressive thyroid cancer compared to those with an identified mutation (12.6% vs 44.3%, P<0.01). Conclusion: BRAFV600E mutations were associated with thyroid cancer subtypes known to be more aggressive. These findings may help thyroid specialists better identify aggressive thyroid nodules associated with indeterminate Bethesda categories.