Background: Previously, fine-needle aspiration biopsy was recommended for any thyroid nodule >1.0 cm in size. In 2015, the American Thyroid Association (ATA) introduced a pattern-based approach for biopsy recommendations based on size and ultrasound (US) characteristics. In 2016, the American College of Radiology (ACR) published the Thyroid Imaging Reporting and Data System, using a point-based system that assesses risk of US characteristics. Methods: This study aims to compare recommendations for thyroid nodule biopsy between the ATA and ACR systems and identify outcomes of nodules with discordant recommendations (DRs). US characteristics, fine-needle aspiration biopsy, and surgical pathology results were evaluated for all patients with >1.0 cm thyroid nodules treated at a single tertiary-care institution from 2010 to 2018. Results: Inclusion criteria were met by 1100 nodules from 687 patients; 42.8% (n = 471) had DR between the ATA and ACR guidelines. All (100%) DR nodules were not recommended for biopsy by ACR, though 53% were recommended to have follow-up. A majority (79%) of DR nodules were recommended for biopsy by ATA, with the remaining 21% recommended for follow-up. Among surgically excised DR nodules (n = 292), 10.3% (n = 30) nodules were found to be malignant, with the vast majority (90.3%) being well-differentiated carcinoma. Among malignant nodules, the ACR would not have recommended biopsy or follow-up for 26.7% (n = 8). Conclusions: The ACR classification system is more restrictive compared with the ATA system for recommending thyroid nodule biopsy. This discrepancy could result in confusion for clinicians and delay in diagnosis or therapy for patients with thyroid cancer.