This multicenter, observational, real-world clinical experience study examined the likelihood of patients with indeterminate thyroid nodules to undergo surgery or have malignant outcomes based on multiplatform combination mutation and microRNA testing (MPT). MPT assessed mutations in BRAF, HRAS, KRAS, NRAS, and PIK3CA genes, PAX8/PPARγ, RET/PTC1, and RET/PTC3 gene rearrangements, and the expression of 10 microRNAs. Kaplan Meier analysis for cumulative probability of survival without having a surgical procedure or malignant diagnosis over the course of patient follow-up was determined for MPT results of 180 patients, of which only 14% had malignancy. A negative MPT result in nodules with Bethesda III or IV cytology (2009) conferred a high probability of non-surgical treatment, with only 11% expected to undergo surgery and a high probability of survival without malignancy (92%) for up to 2 years follow-up. A positive MPT result conferred a 57% probability of malignancy and was an independent risk factor for undergoing surgical treatment (Hazard Ratio [HR] 9.2, 95% confidence intervals 5.4-15.9, P<0.0001) and for malignancy (HR 13.4, 95% confidence intervals 4.8-37.2, P<0.0001). For nodules with weak driver mutations, positive microRNA test results supported high risk of cancer while negative results downgraded cancer risk. The study concluded that MPT results are predictive of real-world decisions to surgically treat indeterminate thyroid nodules, with those decisions being appropriately aligned with a patient’s risk of malignancy over time.