Background: The “obesity paradox” refers to increase cancer risk in obesity with paradoxical improved outcomes. This phenomenon was previously reported in melanoma patients on immunotherapy; however, results are uncertain. Immune checkpoint inhibitors (ICI) are the mainstay of melanoma treatment. There is a lack of real-world data on the impact of body mass index (BMI) on overall survival (OS) and immunotherapy-related adverse events (irAEs) in melanoma patients on ICI. Methods: Data were retrospectively collected from an electronic health record database (TriNetX) which includes over 89 million patients from 56 healthcare systems in the United States. We identified adults with melanoma who received ICI; pembrolizumab, nivolumab, or a combination of ipilimumab and nivolumab between 2012 and 2022. Patients were stratified based on the WHO body mass index (BMI) classification. Overweight and obese patients were 1:1 propensity score-matched for age, sex, race, and use of ICI, with patients with normal BMI. Results: Ourcohort included 11,656 melanoma patients on ICI. 62% were males, 91% were white, and 86% were non-Hispanics. OS was significantly improved in overweight and obese compared to normal BMI patients (HR 0.72, 95% CI, 0.60-0.86; P < 0.001, and HR 0.53, 95% CI, 0.43-0.65); P < 0.001, respectively). Nearly one-third of all weight categories had an irAE. Skin toxicity was the most common, 16.5%-18.2%, while pneumonitis was the least common, 1.0% -2.0%. There was no statistically significant difference between the groups in all included irAE; skin toxicities, thyroid dysfunction, colitis, pneumonitis, or hepatitis. Conclusions: This is the largest real-world data study describing the association between weight status and the outcomes of ICI in melanoma. Our study showed that overweight and obese melanoma patients treated with single or combination ICI had a significantly improved OS compared to patients with normal BMI, in keeping with the “obesity paradox” phenomenon. Intriguingly, high BMI wasn’t associated with an increased risk of irAE. Studies to clarify the underlying mechanisms in melanoma and other malignancies are needed.