Background: Recent studies suggest that obesity is linked to improved progression-free and overall survivals in patients treated with Immune-Checkpoint Inhibitors (ICI). Studies have also shown that irAEs occurrence following ICI infusion is associated with improved survival. Current evidence on the relationship between obesity and the risk of irAEs has been inconclusive. We aimed to assess the impact of obesity on the risk of irAEs after ICI infusion using data from a large retrospective cohort. Methods: The study included newly diagnosed stage I-VI cancer patients treated with ICIs between 2012 and 2021 at the Ohio State University Comprehensive Cancer Center. Patients’ body mass index (BMI) data at or before ICI infusion were classified into normal <25.0 Kg/M², 25 to < 30 Kg/M² overweight and obese ≥ 30 Kg/M². An incident irAE was defined as any gastrointestinal, pulmonary, dermatological, endocrine or hepatobiliary irAEs following ICI infusion. Cox proportional hazard models were fitted to test the associations between obesity and 1) any irAEs and 2) organ-specific irAEs. We evaluated the dose-response association between BMI and irAEs using a three-knot restricted cubic spline in the adjusted Cox proportional models. Results: A total of 4,761 patients were included in the study with a median age of 62 years, 59.2% males and 89% White non-Hispanics. An estimated 34.7%, 31.5% and 33.8% of patients had normal, overweight, and obese BMIs. The median time to incident irAEs was 4.3 months. An estimated 2,791 (58.6%) experienced an irAE, with 28.8% having gastrointestinal, 17.7% pulmonary, 23.7% dermatological, 21.8% endocrine, and 4.4% hepatobiliary irAEs. BMI was a significant predictor of increased risk of irAEs, adjusted hazard ratio (aHR) 1.08 (95%CI: 0.98 to 1.19) overweight vs. normal BMI and aHR 1.17 (95% CI: 1.06 to 1.28) obese vs. normal BMI. In the organ-specific irAEs models, obese vs. normal BMI patients had higher risks of gastrointestinal aHR 1.23 (95% CI: 1.07 to 1.41), dermatological aHR 1.25 (95% CI: 1.07 to 1.28), and hepatobiliary aHR 1.61 (95% CI: 1.11 to 2.36) irAEs. A dose-response was observed in the relationship between BMI and the risk of irAEs whereby patients with BMIs lower than 22 Kg/M² (median normal BMI range 18.5-24.9 Kg/M²) had lower risks of irAEs [BMI 18.5 Kg/M² vs. 22 Kg/M², aHR 0.93 (95% CI, 0.88 to 0.97)] and those with BMIs higher than 22 Kg/M² had higher risks of irAEs [BMI 30 Kg/M² vs. 22 Kg/M², aHR 1.19 (95%CI, 1.09 to 1.29)] and [BMI 40 Kg/M² vs. 22 Kg/M², aHR 1.22 (95% CI, 1.11 to 1.34)]. Conclusions: Among patients treated with ICIs, higher BMI was significantly associated with an increased risk of irAEs. Patients with obesity should be monitored for symptom management following ICIs infusion. Our findings help to explain the previously reported benefits of increased BMI and higher irAEs rates on improved survival.