Background Risk stratification systems for thyroid nodules are often complicated and affected by low specificity. Continual improvement of these systems is necessary to reduce the number of unnecessary thyroid biopsies. Purpose To use artificial intelligence (AI) to optimize the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS). Materials and Methods A total of 1425 biopsy-proven thyroid nodules from 1264 consecutive patients (1026 women; mean age, 52.9 years [range, 18-93 years]) were evaluated retrospectively. Expert readers assigned points based on five ACR TI-RADS categories (composition, echogenicity, shape, margin, echogenic foci), and a genetic AI algorithm was applied to a training set (1325 nodules). Point and pathologic data were used to create an optimized scoring system (hereafter, AI TI-RADS). Performance of the systems was compared by using a test set of the final 100 nodules with interpretations from the expert reader, eight nonexpert readers, and an expert panel. Initial performance of AI TI-RADS was calculated by using a test for differences between binomial proportions. Additional comparisons across readers were conducted by using bootstrapping; diagnostic performance was assessed by using area under the receiver operating curve. Results AI TI-RADS assigned new point values for eight ACR TI-RADS features. Six features were assigned zero points, which simplified categorization. By using expert reader data, the diagnostic performance of ACR TI-RADS and AI TI-RADS was area under the receiver operating curve of 0.91 and 0.93, respectively. For the same expert, specificity of AI TI-RADS (65%, 55 of 85) was higher (P < .001) than that of ACR TI-RADS (47%, 40 of 85). For the eight nonexpert radiologists, mean specificity for AI TI-RADS (55%) was also higher (P < .001) than that of ACR TI-RADS (48%). An interactive AI TI-RADS calculator can be viewed at http://deckard.duhs.duke.edu/∼ai-ti-rads . Conclusion An artificial intelligence-optimized Thyroid Imaging Reporting and Data System (TI-RADS) validates the American College of Radiology TI-RADS while slightly improving specificity and maintaining sensitivity. Additionally, it simplifies feature assignments, which may improve ease of use. © RSNA, 2019 Online supplemental material is available for this article.