Background: Data on HCRU and costs in US UC patients treated with ICIs is in its infancy, as there is little information by LOT or focused on irAEs due to ICI use. In addition, the relationship between irAEs and mortality is controversial, with some studies suggesting lower risk of mortality in pts with irAEs, whereas others have found no association between irAEs and mortality. We assessed the associations of 1) irAEs and 2) LOT with HCRU, costs, and mortality in UC pts treated with ICI monotherapy. Methods: This retrospective cohort study used administrative claims data linked with mortality data from the National Death Index and Social Security Death Index to identify US commercial and Medicare Advantage plan members with UC treated with ICI monotherapy between 1 Sep 2014 and 30 Apr 2019. The LOT number of ICI therapy was captured. Twenty-one irAEs were chosen a priori based on ASCO and NCCN guidelines and clinical input. Based on ICD codes from claims, newly occurring irAEs were captured from ICI initiation to the earliest of 6 months after initial ICI LOT ended, start of new treatment, death, disenrollment, or 30 Apr 2019; HCRU and costs were assessed during same time. Using Cox regression with ICI LOT and time-varying irAEs as the exposures, we computed adjusted hazard ratios (HRs). Lin’s regression analysis was used to calculate adjusted 6-month all-cause costs by irAE. Results: Among UC pts treated with ICI monotherapy (N=417; mean age 74 ± 10 years; 72% male; 17% received prior systemic steroids; 32% initiated ICI as LOT 1, 43% as LOT 2), 22% (n=90) had an irAE. Pts who received ICIs as 2L therapy were 1.5 (95% CI: 1.1-2.0) and 1.7 (95% CI: 1.2-2.4) times more likely to have an all-cause ER visit and inpatient stay, respectively, than those who received 1L. There was no difference in mortality risk between 2L and 1L subgroups (HR, 1.2 [95% CI: 0.9-1.6]). Pts with irAEs had a 60% higher risk of an all-cause ER visit (95% CI: 1.0-2.5) and more than double the risk of an all-cause inpatient stay (HR, 2.6 [95% CI: 1.7-4.0]) than pts without irAEs. Pts who experienced an irAE had higher mean all-cause healthcare costs over 6 months vs those without irAEs ($98,415 vs $75,300; p<0.001). Mortality rates were similar between UC pts with and without irAEs (HR, 1.2 [95% CI: 0.9-1.6]). Conclusions: Pts with irAEs had higher all-cause HCRU and costs than pts without, and pts who received ICIs as 2L therapy had higher HCRU and costs than those who received 1L. This real-world study did not find that irAEs were associated with mortality in UC pts treated with ICI monotherapy. To inform optimum use of ICIs and management of irAEs, future work should include longer follow-up and grade of severity and number of irAEs.