e16372 Background: Acute ischemic stroke, marked by a sudden loss of brain blood supply, carries potential life-threatening consequences. The impact on individuals with pre-existing gastrointestinal (GI) malignancies, coupled with ensuing complex medical complications affecting morbidity and mortality, remains inadequately understood. This study aims to assess the influence of acute ischemic stroke on in-hospital mortality in GI cancer patients in the United States. Methods: This retrospective analysis utilized the 2016-2020 National Inpatient Survey (NIS) database. Adults aged 18 and above with esophageal, gastric, colon, cholangiocarcinoma, hepatocellular carcinoma, and pancreatic cancers were identified using the International Classification of Disease-10 (ICD-10) code. The cohort was stratified into patients with and without acute ischemic stroke. Hospital mortality was analyzed using STATA 18, adjusted for age, gender, race, insurance, Charlson’s index, baseline hospital characteristics, and comorbidities. Multivariate logistic regression analysis was performed, with all P values ≤ 0.05 considered statistically significant. Results: Among 2,133,465 adults with GI malignancies, 28,394 were hospitalized with acute ischemic stroke. Patients with acute ischemic stroke were older (mean age 71.19 vs. 67.01 years; P < 0.001), more likely to be male (55.47%, P = 0.002), Caucasian (67.96%, P < 0.001), from urban teaching hospitals (76.83%, P = 0.011), and had Medicare insurance (70.50%, P < 0.001). Acute ischemic stroke was most associated with pancreatic cancer (39.81%), colon cancer (30.13%), and esophageal cancer (9.86%). Within the cohort of patients with acute ischemic stroke, esophageal cancer patients had the highest mortality rates of 20%. After adjusting for potential confounders, patients with colon cancer, esophageal cancer, gastric cancer, pancreatic cancer, cholangiocarcinoma, and hepatocellular carcinoma had significantly higher odds of in-hospital mortality of 2.91, 2.50, 2.31, 2.22, 1.65, and 1.51, respectively. Conclusions: This study reveals an association between outcomes in hospitalized GI cancer patients and acute ischemic stroke, leading to increased mortality despite adjusting for potential confounders. The impact of anticancer therapies on the vascular system may influence the risk and severity of ischemic events. Further studies are needed to develop tailored prevention, diagnosis, and management strategies to reduce disease complications and the overall healthcare burden of cerebrovascular events.