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Background: Analysis of cytologically indeterminate thyroid nodules with Afirma Gene Expression Classifier (GEC) and Genomic Sequencing Classifier (GSC) can reduce surgical rate and increase malignancy rate of surgically resected indeterminate nodules., Methods: Retrospective cohort analysis of all adults with cytologically indeterminate thyroid nodules from January 2013 through December 2019. We compared surgical and malignancy rates of those without molecular testing to those with GEC or GSC, analyzed test performance between GEC and GSC, and identified variables associated with molecular testing., Results: 468 indeterminate thyroid nodules were included. No molecular testing was performed in 273, 71 had GEC, and 124 had GSC testing. Surgical rate was 68% in the group without molecular testing, 59% in GEC, and 40% in GSC. Malignancy rate was 20% with no molecular testing, 22% in GEC, and 39% in GSC ( P = 0.022). GEC benign call rate (BCR) was 46%; sensitivity, 100%; specificity, 61%; and positive predictive value (PPV), 28%. GSC BCR was 60%; sensitivity, 94%; specificity, 76%; and PPV, 41%. Those with no molecular testing had larger nodule size, preoperative growth of nodules, and constrictive symptoms and those who underwent surgery in the no molecular testing group had higher body mass index, constrictive symptoms, higher Thyroid Imaging Reporting and Data System and Bethesda classifications. Type of provider was also associated with the decision to undergo surgery., Conclusion: Implementation of GEC showed no effect on surgical or malignancy rate, but GSC resulted in significantly lower surgical and higher malignancy rates. This study provides insight into the factors that affect the real-world use of these molecular markers preoperatively in indeterminate thyroid nodules., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)