Background: Upper gastrointestinal bleeding associated with esophagogastric varices (EGV) is a morbid and potentially deadly complication of advanced hepatocellular carcinoma (aHCC). However, the presence of EGV among the aHCC population receiving esophagogastroduodenoscopy (EGD) in the US is not well understood, nor are the predictors of EGV- or bleeding-related ER or hospitalization (the outcome) among those who are newly initiated on systemic treatment. Methods: A retrospective cohort analysis was conducted utilizing IQVIA’s PharMetrics Plus Health Plans Claims database (January 1, 2016, to July 31, 2021). Patients ≥18 years of age with ≥1 prescription for an aHCC systemic treatment were included; the date of the first prescription was the index date. At least 12 months of continuous enrollment pre-index and 6 months post-index (unless patients were deceased) were required. Patients with pre-index diagnosis codes for renal cell carcinoma, differentiated thyroid carcinoma, colorectal cancer, gastric cancer, non-small cell lung carcinoma, and liver transplant were excluded. Logistic regression was conducted to identify associations between baseline characteristics and the outcome. Results: A total of 904 patients with aHCC were included (mean age: 61.3 years; 75.3% male); 39.4% of patients died within 6 months following the index date. During the pre-index period, 688 (76.1%) patients had portal hypertension-related comorbidity, 327 (36.2%) had EGD, 122 (13.5%) had EGV, and 63 (7.0%) had bleeding. During the observational period, 458 (50.7%) patients received EGD, among whom 209 (45.6%) also had EGV. 141 (15.6%) patients had ≥1 outcome event during the post-index period. In the adjusted analysis, patients with pre-index bleeding and with EGV but no bleeding had 4.5- and 3.1-times higher odds of having post-index outcome, respectively, as compared with those lacking pre-index bleeding and EGV. Moreover, the pre-index presence of portal hypertension-related comorbidities was associated with 3.1 times greater odds of having a post-index outcome. Conclusions: EGV and bleeding events are common in patients with aHCC receiving systemic therapies. The EGV prevalence of 45.6% among those receiving EGD is consistent with prior similar studies outside of the US (Giannini EG, et al. Clin Gastroenterol and Hepatol. 2006; Iavarone M, et al. United European Gastroenterol J. 2016; Hsieh WY, et al. Sci Rep. 2017). The presence of bleeding, EGV, and portal hypertension-related comorbidities prior to treatment initiation were associated with the increased post-treatment risk of EGV- or bleeding-related ER or hospitalization in these patients. To our knowledge, this is the first study to assess and report the presence of EGV among those receiving EGD in a US aHCC population.