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BACKGROUND AND OBJECTIVES: The increase in neonatal abstinence syndrome (NAS) has underscored the need for NAS surveillance programs, but many rely on passive surveillance using unverified diagnosis codes. Few studies have evaluated the validity of these codes, and no study has assessed the recently proposed Council of State and Territorial Epidemiologists (CSTE) case definition. The Florida Birth Defects Registry investigated the accuracy of International Classification of Diseases, 10th Revision, Clinical Modification codes related to NAS (P96.1 and P04.49) and assessed the sensitivity of the CSTE case definition. METHODS: We identified a sample of infants born during 2016 coded with P96.1 and/or P04.49. Record review was completed for 128 cases coded with P96.1, 68 with P04.49, and 7 with both codes. Lacking consensus regarding a gold standard definition of NAS, we used clinical data to classify each case using the Florida and CSTE definitions. The code-specific accuracy was measured by using the positive predictive value (PPV). The clinical characteristics indicative of NAS were compared for case classification based on both definitions. RESULTS: By using the Florida definition, the overall PPV was 68% but varied by code: 95.3% for P96.1 and 13.2% for P04.49. The overall (47.8%) and code-specific PPVs were lower by using the CSTE definition. Comparison of clinical characteristics demonstrated that 60.7% of cases classified as no NAS by using the CSTE definition had robust clinical signs of NAS. In our sample, the CSTE case definition underestimated NAS prevalence. CONCLUSIONS: Only the P96.1 International Classification of Diseases, 10th Revision, Clinical Modification code displayed high accuracy. Discordance in NAS case definitions and surveillance methodologies may result in erroneous comparisons and conclusions that negatively impact NAS-related surveillance and research. [ABSTRACT FROM AUTHOR]