BACKGROUND: Vismodegib and sonidegib are currently the only Hedgehog inhibitors (HHIs) approved by the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced BCC (laBCC). However, there is limited systematic research comparing the adverse drug events (ADEs) associated with these two inhibitors. RESEARCH DESIGN AND METHODS: Data were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) for the period from 2019 to the second quarter of 2024. Disproportionality analysis was conducted to compare ADEs between vismodegib and sonidegib. RESULTS: The occurrence of ADEs was notably higher among patients aged ≥ 65 years (72.98%) and males (60.17%). The most frequently reported ADEs associated with HHIs included skeletal muscle and joint diseases and nervous system disorders, particularly muscle spasms and dysgeusia. Differences in adverse reactions between vismodegib and sonidegib were observed, mainly in nervous system, gastrointestinal system, skin and subcutaneous tissue, and renal and urinary disorders. CONCLUSIONS: This analysis, using the FAERS database, enhances understanding of the ADE profiles associated with both vismodegib and sonidegib. Further research is needed to validate the hypotheses generated by this study.