© 2019 RSNA. 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 TIRADS (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.