Background Long-acting Gonadotropin-releasing hormone analogs(GnRHa), including leuprolide, goserelin, histrelin, buserelin, triptorelin, have been widely used for a variety of diseases including prostate cancer, breast cancer, endometriosis, uterine leiomyomas, and central precocious puberty. However, their real-world safety profile differences have not been adequately compared. Objective: We aimed to investigate the adverse event (AE) profile differences of long-acting GnRHa reported by the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: All indications were searched long-acting GnRHa, as primary suspect drugs, from FAERS data (January 2004 to September 2023). We performed disproportionality analyses by reporting odds ratios (ROR) and conducted univariate and multivariate logistical regression analyses to determine the odds ratio (OR) of serious AEs associated with long-acting GnRHa under different exposure factors. Results: Reproductive system and breast disorders possessed the greatest proportion in AEs of the five long-acting GnRHa. Buserelin and histrelin demonstrated a higher percentage of AEs in the gastrointestinal and psychiatric disorders separately, which also exhibited a higher risk of important medical events in logistic regression analysis and the risk was lower in patients under 18 years old than those over 18 . Conclusions：Significant disparities exist between the adverse event profiles of long-acting GnRHa.The identification of high-risk factors and the enhancement of AEs monitoring are crucial during clinical application.