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Simple Summary: Thyroid cancer is the most prevalent endocrine malignancy. Thyroid molecular testing is a tool that can help better understand the nature of thyroid tumors. Thyroid nodules are scored on a Bethesda scale from I–VI based on the likelihood of malignancy. Bethesda III and IV nodules are classified as indeterminate; in other words, there is uncertainty as to whether they are benign or malignant. This study analyzes how molecular testing can help to identify specific molecular mutations, copy number alterations, and gene expression profiles within indeterminate thyroid nodules to have a better understanding of them. This will lead to more effective and optimal treatment plans. Molecular testing is a valuable tool that has been well researched with respect to the invasiveness/aggressiveness of nodules and their associations with specific molecular mutations and alterations. Molecular testing was used in this study to evaluate Bethesda III and IV nodules and highlight any patterns, trends, and differences observed between the two groups. Background: Thyroid cancer is the most common endocrine malignancy, and accurate diagnosis is crucial for effective management. Fine needle aspiration cytology, guided by the Bethesda System for Reporting Thyroid Cytopathology, categorizes thyroid nodules into six categories, with Bethesda III and IV representing indeterminate diagnoses that pose significant challenges for clinical decision-making. Understanding the molecular profiles of these categories may enhance diagnostic accuracy and guide treatment strategies. Methods: This study retrospectively analyzed data from 217 patients with Bethesda III and IV thyroid nodules who underwent ThyroSeq v3 molecular testing followed by thyroid surgery at McGill University teaching hospitals. The analysis focused on the presence of specific molecular mutations, copy number alterations (CNAs), and gene expression profiles (GEPs) within these nodules. The relationship between these molecular findings and the clinico-pathological features of the patients was also examined. Results: This study identified notable differences in the molecular landscape of Bethesda III and IV thyroid nodules. Bethesda IV nodules exhibited a higher prevalence of CNAs and distinct GEPs compared to Bethesda III nodules. Interestingly, the BRAFV600E mutation was found exclusively in Bethesda III nodules, which correlated with more aggressive malignant behavior. These findings underscore the potential of molecular profiling to differentiate between the clinical behaviors of these indeterminate nodule categories. Conclusions: Molecular profiling, including the assessment of CNAs, GEPs, and specific mutations like BRAFV600E, provides valuable insights into the nature of Bethesda III and IV thyroid nodules. The distinct molecular characteristics observed between these categories suggest that such profiling could be instrumental in improving diagnostic accuracy and tailoring treatment approaches, ultimately enhancing patient outcomes in thyroid cancer management. [ABSTRACT FROM AUTHOR]