Objective To investigate the difference in infarction characteristics between large artery atherosclerosis and cardioembolism acute ischemic stroke (AIS). Methods A retrospective study was done on 99 AIS patients, who were admitted to Emergency Room of our hospital and underwent multi-modal computed tomography (CT) after admission and before treatment. Forty-six of 99 AIS patients had large artery atherosclerosis and 53 had cardioembolism. The NIHSS score and GCS score on admission, infraction core and ischemic penumbra volumes and the volume difference, and vascular occlusion rates of posterior circulation and large artery were compared between the two groups. Results Compared with the cardioembolism group, the NHISS score was significantly lower and the GCS score was significantly higher in the large artery atherosclerosis group (9.5[2.0, 16.0] vs 15.0[6.0, 24.0], Z=2.31, P<0.001; 13.52±2.69 vs 11.60±3.31, t=1.04, P=0.002). The volumes of infarction core and ischemic penumbra in the cardioembolism group were 1 (0, 22) mL and 64 (30, 126) mL, respectively, and were both significantly larger than those in the large artery atherosclerosis group (0[0, 1] mL and 10[0, 70] mL; Z=3.85 and 3.43, both P<0.01). However, the volume difference of ischemic penumbra and infraction core was not significantly different between the cardioembolism and large artery atherosclerosis groups (46[4, 103] mL vs 10[0, 64] mL, Z=1.92, P>0.05). The large artery occlusion rate and posterior circulation occlusion rate were both significantly different between the large artery atherosclerosis and cardioembolism groups (30.43%[14/46] vs 50.94%[27/53] and 36.96%[17/46] vs 9.43%[5/53]; χ²=11.82 and 6.77, both P<0.001). Conclusion The clinical symptoms, cerebral changes and intracranial large artery changes are different in AIS patients with large artery atherosclerosis and cardioembolism. Etiology evaluation based on clinical features and multi-modal CT examination can help to accurately assess the ischemic state of AIS patients.