Nivolumab combined with ipilimumab (NIVO-IPI) and nivolumab combined with relatlimab (NIVO-RELA) are approved treatments for advanced melanoma. However, the data on the differential adverse event (AE) risks associated with these two regimens are lacking.We performed a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database for NIVO-IPI and NIVO-RELA from the fourth quarter (Q4) of 2015 to Q4 of 2024. We calculated the reporting odds ratios (ROR) and information component (IC) with 95% confidence intervals (CIs).A total of 7,482 records for NIVO-IPI and 185 records for NIVO-RELA were extracted from FAERS. NIVO-IPI showed significantly higher risks for gastrointestinal (ROR = 1.39), endocrine (ROR = 3.10), hepatobiliary (ROR = 2.32), metabolism and nutrition (ROR = 1.44), and respiratory, thoracic, and mediastinal disorders (ROR = 1.18), particularly in preferred terms (PTs) such as colitis, hypophysitis, pneumonia, and hepatitis. NIVO-RELA was associated with increased risks for cardiac (ROR = 2.84) and vascular disorders (ROR = 2.04), notably in PTs like myocarditis, troponin elevation, and myasthenia gravis. 80% of AEs occurred within three months for both regimens. The median time-to-onset was 42 days for NIVO-IPI compared to 57 days for NIVO-RELA, with no statistically significant difference (p = 0.66).NIVO-IPI is linked with a broader range of immune-related toxicities, whereas NIVO-RELA presents higher cardiac-specific risks. These findings emphasize the need for tailored AE monitoring based on treatment selection.© 2025. The Author(s).