BACKGROUND: Lamotrigine (LTG), a medication frequently prescribed for epilepsy. Despite its widespread use, there remains a lack of clarity regarding the drug's safety profile when used over extended periods in large patient populations. This study evaluated the safety profile of LTG using the FDA Adverse Event Reporting System (FAERS), aiming to enhance clinical decision-making. RESEARCH DESIGN AND METHODS: We used disproportionate analyses, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), to identify signals of adverse reactions associated with LTG. RESULTS: A total of 187,024 records were reported, involving 905 adverse drug event (ADE) signals across 27 system organs classes (SOCs). We detected several known adverse event (AE) signals from the clinical trial phase, including seizures, rash, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Additionally, we uncovered several unforeseen and significant adverse effects that were not documented in the medication's prescribing information, encompassing suicides, atrial septal defects, Brugada syndrome, and signals associated with aortic stenosis. CONCLUSIONS: Our analysis in the post-marketing setting reveals new AE signals associated with LTG, highlighting the need for ongoing risk surveillance.