Background: IrAEs associated with immune checkpoint inhibitors (ICIs) can result in morbidity and mortality. The incidence, spectrum, and risk factors for irAEs are usually reported from retrospective studies and clinical trials, which typically exclude patients (pts) with pre-existing autoimmune disease (AD). The prevalence and risk factors for irAEs in a diverse, pan-tumor, real-world setting is not well understood. Methods: From 06/2021 to 2/2023, we prospectively enrolled pts receiving ICIs (alone or in combination as standard-of-care) at a tertiary care center in this imCORE network study. Univariate and multivariate logistic regressions and survival curves were used to interrogate risk factors for irAE development and the relationship between irAEs, graded using CTCAE v5.0, and clinical response by RECIST 1.1. Results: 132 pts with prior ICI therapy were prospectively followed. Median age was 65 years (IQR 56-72), 35% were female, 69% were white, and 24% were black. Most common tumor histologies were: hepatocellular, renal cell, bladder, non-small cell lung, and head and neck carcinoma. 23% (n=30/132) received dual ICI (nivolumab+ipilimumab). In the whole cohort, 36.4% (n=48/132) of pts developed any-grade irAE and 10.6% (n=14/132) developed a severe irAE (grades 3-5). There were 2 fatal irAEs (n=1 hepatitis, n=1 myocarditis) representing 1.5% of the total cohort. The median time to first irAE was 1.8 months (mos; IQR 1.2-3.1) for anti-PDL1 monotherapy, 1.2 mos (IQR 0.7-2.2) for dual ICI, 4.4 mos (0.2-8.7) for PDL1+chemotherapy, and 2.1 mos (1.3-3.1) for PDL1+other. A subgroup of pts (10.6%; n=14/132) had pre-existing AD and 50% (n=7/14) had ever received immunosuppression for their AD. Among pts with AD, the incidence of irAEs was 57% (n=8/14) vs 33.9% (n=40/118) among those without AD. Antitumor response for pts with AD was 27.3% vs 25.8% those without AD. Receipt of dual ICI therapy was associated with increased risk of any-grade irAE (OR 2.87 p=0.02) and severe irAE (OR 40.9 p=0.004). Pts with any grade irAEs were significantly more likely to experience a partial/complete response vs pts without irAEs (OR 4.14 p=0.02) and this relationship was preserved after adjustment for single vs dual ICI. Pts who did not develop irAEs had an overall response rate (ORR) of 18.2%, mPFS of 3.5 mos (IQR 1.6-7.3), and mOS 7.3 mos (IQR 3.8-9.9) vs pts who developed any grade irAE who had an ORR of 37.8%, mPFS of 5.9 mos (IQR 3.3-8.8), and mOS 8.6 mos (IQR 4.9-11.4). Conclusions: In this pan-tumor, prospective cohort study of pts receiving ICI therapy in a real world setting, we identified that pts with pre-existing AD and those on dual ICI had increased risk of irAE development. This signals the need for closer monitoring, early recognition, and management of irAEs in these pts. In addition, pts who developed irAEs were more likely to experience partial or complete response in a diverse tumor cohort.