<h3>Objective:</h3> To determine whether delirium in acute ischemic stroke is localizable to specific neural networks. <h3>Background:</h3> Delirium is estimated to occur in one-fourth of patients with acute stroke. Despite its associated morbidity and mortality, prediction and pathophysiological understanding of delirium remains challenging. A recent meta-analysis of patients with delirium and stroke found increased risks of delirium in supratentorial, cortical, and anterior circulation strokes, raising the possibility of an underlying neural network for delirium. <h3>Design/Methods:</h3> We performed a retrospective cohort study of patients admitted to a comprehensive stroke center with acute ischemic stroke from January 2016 to April 2019. Patients were assessed for delirium by trained clinical nursing staff using the Confusion Assessment Method (CAM) framework. Acute stroke lesions from MRI diffusion weighted images (DWI) lesions were automatically segmented using a machine learning algorithm. Lesions were registered to a 2mm Montreal Neurological Institute template (MNI-152). We then used lesion network mapping to identify potential unifying brain networks for delirium in patients with acute stroke. <h3>Results:</h3> 907 scans from unique patients were analyzed. 274 patients had delirium (30.2%), 47.5% were women (431), and the mean age was 69.6 years old. In comparison to a general stroke cohort, patients with delirium had lesions connected to the right and left inferior frontal gyri and left middle temporal gyrus and left temporo-parietal junction (one-sample t-test, family-wise error p<0.05). Sensitivity analysis showed that delirium was not associated with parietal, occipital, brainstem, and cerebellar lesions. <h3>Conclusions:</h3> Delirium in stroke localizes to a network connected to frontotemporal regions. These results have implications for prediction of delirium in patients with acute stroke, with the potential for targeting multimodal prevention. Future work will refine their specificity, however, the results suggest that frontotemporal networks may be particularly important for cardinal symptoms of delirium, a disorder of impaired attention and awareness <b>Disclosure:</b> Dr. Rhee has stock in NTAP. Dr. Rhee has stock in TSLA. Dr. Rhee has stock in BABA. Dr. Rhee has stock in ZM. Dr. Rhee has stock in GM. Dr. Rhee has stock in PFF. Dr. Rhee has stock in AMZN. Dr. Rhee has stock in META. Dr. Rhee has stock in GE. Dr. Rhee has received publishing royalties from a publication relating to health care. Dr. Rhee has received personal compensation in the range of $0-$499 for serving as a Director of the Hippocratic Forum with Abigail Adams Institute. Dr. Ferguson has nothing to disclose. Dr. Bonkhoff has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NeuroImage Clinical (Elsevier). Mr. Patel has nothing to disclose. Dr. Bretzner has nothing to disclose. Dr. Hong has nothing to disclose. Dr. Ryan has nothing to disclose. Dr. Westover has stock in Beacon Biosignals. The institution of Dr. Westover has received research support from NIH. Dr. Westover has received publishing royalties from a publication relating to health care. Dr. Westover has a non-compensated relationship as a cofounder with Beacon Biosignals that is relevant to AAN interests or activities. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley. Dr. Rost has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Stroke - AHA/ASA Journal. The institution of Dr. Rost has received research support from NIH. Dr. Rost has received publishing royalties from a publication relating to health care. The institution of Dr. Kimchi has received research support from NIH. The institution of an immediate family member of Dr. Kimchi has received research support from NIH.