Background: Immune checkpoint inhibitors are revolutionizing cancer care and providing new treatment options with promising outcomes for many cancers. However, immune-related adverse events (irAEs) are not infrequent and can be severe. An intriguing relationship between the presence of irAEs and treatment efficacy has been described but lacks thorough characterization. We aimed to further elucidate a relationship between immune checkpoint inhibitor (ICI) irAEs and efficacy. Methods: We identified cancer patients treated with ICI from 2015-2021 across two institutions: Michael E DeBakey Veterans Affairs Medical Center (MEDVAMC) and Baylor St. Luke’s Medical Center (BSLMC). Clinical data including cancer type, irAEs type and grade, ICI response, progression free survival (PFS) and overall survival (OS) was collected. Using the Kaplan Meier method, survival curves were generated and comparisons were made amongst groups using the log-rank test. Fisher’s exact test was used to compare progression of disease between groups. To determine if variables were associated with survival, multivariable Cox regression analysis was used. Results: Of the 456 patients treated with ICI, irAEs were seen in 165 (36%) patients. Of these, 81 (49%) patients had grade 1 toxicities, most commonly arthritis, diarrhea, and dermatitis. 47 (28%) patients had grade 2 toxicities (colitis, hypothyroidism, adrenal insufficiency). 34 (21%) patients had grade 3 toxicities (pneumonitis, pancreatitis, hepatitis). 3 patients had grade 4 toxicities (pneumonitis, DRESS syndrome, and hepatorenal syndrome). 1 patient expired and 24 (15%) patients discontinued ICI due to irAEs. 55 (33%) of patients with irAEs were treated with steroids. For patients assessed for efficacy, objective response rate (ORR) to ICI was higher in patients with irAEs [47% (12% CR) vs 33% (11% CR)]. In fact, the presence of any irAEs was significantly likely to predict response to ICI (OR 1.90, 95% CI 1.25 - 2.86, p = 0.0026). In a subset of patients evaluable for survival (n = 375), patients with any irAEs had a significantly improved median PFS compared to those without irAEs (9.0 vs. 4.8 months, p = 0.0018). Multivariable analysis demonstrated that the development of any irAEs was related to a significantly improved OS (HR 0.63, 95% CI 0.43-0.89, p = 0.01). Conclusions: The development of irAEs in cancer patients treated with immunotherapy may predict better treatment efficacy and overall survival. Further prospective studies are needed to confirm these associations and mechanism of action.