Background: Increased body mass index (BMI) has been associated with improved efficacy of immune checkpoint inhibitor therapy (ICI) in cancer patients. We aimed to retrospectively assess the relationship between patient BMI and response to ICI at two unique health care systems in our institution Methods: We identified patients treated with ICI from 2015-2021 at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) Cancer Center and Baylor St. Luke’s Medical Center (BSLMC), a private hospital-based cancer center, both academic affiliates of Baylor College of Medicine. Clinical details, including BMI, and treatment efficacy were collected. We defined BMI categories as follows: underweight ( < 18.5), normal weight (18.5-24.9), overweight (25-29.9), and obese (≥30). Progression free survival (PFS), overall survival (OS), and overall response rate (ORR) were the primary end points calculated for treatment efficacy. Survival curves were generated using the Kaplan-Meier method, and intergroup comparisons were performed with log-rank test. Cox regression analysis was used to determine whether BMI at ICI initiation was associated with survival. Chi-square testing was used to determine any association between BMI and ORR. Results: We identified 430 patients treated with ICI, 257 (60%) from BSLMC and 173 (40%) from MEDVAMC. 341 patients (79%) were male and 89 (21%) female. Cancer types included 127 (30%) lung, 49 (11%) kidney, 40 (9.3%) bladder, 38 (8.8%) melanoma, and 38 (8.8%) mesothelioma, 34 (7.9%) head and neck, and 104 (24%) other. 160 (37%) patients had a normal BMI at ICI initiation, 37 (8.6%) underweight, 132 (31%) overweight, and 101 (23%) obese. Mean BMIs of different cancer types were as follows: lung (24.7), kidney (29.2), bladder (26.0), melanoma (29.9), mesothelioma (25.25), head and neck (23.7). 292 (68%) patients were treated with ICI monotherapy. The ORR for patients with normal vs. obese BMIs treated with ICI were 28% and 42%, respectively (p = 0.03). In a subset of patients evaluable for survival (n = 322), patients with an obese BMI had a significantly improved median PFS compared to those with normal BMI (36.4 vs. 23.5 months, respectively, p < 0.0001). Multivariable analysis demonstrated that patients with an obese BMI had significantly improved overall survival compared to patients with a normal BMI (HR 0.64, 95% CI 0.44-0.91, p = 0.014). This relationship was also seen in the subset of patients treated with ICI monotherapy (HR 0.66, 95% CI 0.45-0.95, p = 0.029). This association was noted regardless of health care systems. Conclusions: Increased BMI in cancer patients treated with ICI may predict better treatment efficacy and survival outcomes. More research is needed to define this relationship more clearly.