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Context: Thyroid nodules of indeterminate cytology can be subjected to molecular testing such as the Afirma Genomic Sequencing Classifier (GSC), thereby minimizing the number of unnecessary diagnostic surgeries., Objective: This work aimed to evaluate and compare the cost of routine GSC testing of indeterminate thyroid nodules in different countries., Design, Patients and Main Outcome Measures: The cost of diagnostic hemithyroidectomy of indeterminate thyroid nodules was calculated by performing a Monte Carlo simulation cost analysis on a Markov decision-analytic model and then compared to that of GSC testing in the UK, Australia, USA, and Israel., Results: Assuming that patients are treated by surgical resection and routine GSC testing is performed for all nodules of indeterminate significance, we found the GSC test to be more cost effective compared with diagnostic hemithyroidectomy when malignancy rates of thyroid nodules are less than 22.6%-37.1%, depending on the country where the test is performed. Given the cost of a thyroidectomy in the UK, Australia and Israel, performing routine GSC tests on all Bethesda IV nodules is more expensive than routine diagnostic hemithyroidectomy and becomes cost effective for Bethesda III when the GSC cost is below 3,031-3,087 USD. In comparison, in the USA, higher cost of thyroidectomy makes the GSC test cost effective for Bethesda III nodules at its current cost, but not for Bethesda IV nodules where it becomes cost effective under the price of 3,031 USD., Conclusions: Different molecular testing and surgical costs in different countries should be considered when performing cost analysis. In addition, since different medical centres have different malignancy rates, personalized in-house assessment of cost-effectiveness is warranted., (© 2021 John Wiley & Sons Ltd.)