The Sentinel Initiative was established in 2008 to monitor the safety of FDA-regulated medical products. This article evaluated the positive predictive value (PPV) of ICD-9 codes for post-vaccination febrile seizures to identify optimal algorithms for use in post-market safety surveillance. The authors identified ICD-9 diagnosis codes for fever and seizures in the emergency department or inpatient setting after vaccinations of interest from July 1, 2010 to June 30, 2011. Medical record review was conducted to verify febrile seizure events. Results indicate that ICD-9 diagnosis codes in the inpatient and emergency department settings have high predictive value for identifying febrile seizures within the Sentinel Distributed Database.