Background: Metastatic UM is associated with a median overall survival (OS) < 1 year (yr) and overall response rate (RR) to ICI < 18%. SF3B1 mut UM represent a clinically unique subset of UM, distinct from BAP1 mut disease, characterized by aberrant spliceosome machinery which may result in increased neoantigen presentation, increased immunogenicity, and sensitivity to ICI. To assess these hypotheses, we performed a multicenter retrospective analysis to assess the natural history and response to ICI in patients (pts) with SF3B1 mut UM. Methods: Patients were identified from institutional databases and the AACR Project GENIE Consortium. Data collected included: baseline and recurrent disease characteristics, molecular characteristics, treatments received, treatment response, and vital status. Efficacy endpoints included investigator assessed RECIST RR and OS. Results: 58 pts with deleterious SF3B1 mutations were identified: 56 R625; 1 D781G; 1 G742D. Median age at diagnosis (dx) was 52 (range, 14-87). 50% were female. 49 pts developed distant metastases. The median time from initial dx to metastasis was 6.1 years (yrs; range, 0.9 to 26.7). Initial metastatic sites (n = 48) were: liver-only (52%); non-liver-only (29%); mixed liver and non-liver disease (19%). The most common initial metastatic sites were: liver (71%), lung (29%), soft tissue (13%), lymph node (8%), and bone (4%). The median OS for all pts from time of metastasis was 3.9 years (95% confidence interval (CI), 2.3-6.2) with OS for pts with non-liver only disease at 6.2 yrs vs those with liver-only or mixed disease at 3.4 yrs (hazard ratio = 2.12, p = 0.14). 1-year OS rate from time of metastasis was 94% (95% CI, 0.86-0.99). 34 pts received ICI for metastatic disease at which time 27% had received a prior systemic therapy (median, 0; range, 0-3) and 35% had received a prior hepatic regional therapy (median, 0; range, 0-6). 15 pts received single-agent anti-PD1; 4 received ipilimumab alone; 15 received dual ICI. 10 pts received ICI with concurrent hepatic regional tx. Best response among 33 evaluable pts were: 9% partial response; 39% stable disease; 52% progressive disease. Median OS from ICI initiation was 20.2 months (95% CI, 13.1-27.4). 1-year OS from ICI initiation was 74% (95% CI, 0.59-0.90). Conclusions: SF3B1 mut UM is characterized by later development of metastases, more common involvement of extrahepatic sites, and longer OS when compared with historical datasets of molecularly unselected UM. Although a modest RR to ICI was observed, the median OS and 1-year survival rate post-ICI are numerically superior to historical controls. Given the more indolent course of SF3B1 mut UM, stratification by SF3B1 status should be included in future clinical trials.