Objective To investigate the clinical features and prognosis of acute isolated corpus callosum infarction. Methods The clinical and imaging data of patients with acute isolated corpus callosum infarction diagnosed in the Department of Neurology of Beijing Geriatric Hospital and the Department of Neurology of China-Japan Friendship Hospital from February 2017 to February 2021 were retrospectively selected. Patients were divided into groups according to infarction location, infarction size and prognosis. According to the infarction location, the patients were divided into single-site lesion group and multi-site lesions group. According to the infarction size, the patients were divided into large lesion group and small lesion group. According to the prognosis, the patients were divided into good prognosis group and poor prognosis group. The clinical characteristics, etiology and prognosis of these diseases were observed and analyzed. Results A total of 52 patients were included. Among them, there were 32 males (61.5%) and 20 females (38.5%), with an average age of (65.4±7.1) years. The most common risk factors were hypertension (44 cases, 84.6%), hyperlipidemia (32 cases, 61.5%), and diabetes (28 cases, 53.8%). The most common infarction site was splenium in the single-site lesion group (24 cases, 46.2%). The vast majority of patients (92.3%) had nonspecific clinical symptoms, and only 4 (7.7%) had corpus callosum disconnection syndrome. In the TOAST etiological classification, Large-artery atherosclerosis (LAA) was the most common (25 cases, 48.1%), followed by small-artery occlusion (14 cases, 26.9%), the responsible vascular lesions were the most common in the P1/P2 segment of posterior cerebral artery (10 cases) and the A1/A2 segment of anterior cerebral artery (9 cases). There was no significant difference in etiology between the groups with different infarction location and the groups with different infarction size (P>0.05). Forty-four cases (84.6%) had a good prognosis, and 8 cases (15.4%) had a poor prognosis. Combined with multiple risk factors, multiple involvement of lesions and large infarction size were associated with poor prognosis (P<0.05). Conclusions Acute isolated corpus callosum infarction is a rare type of ischemic stroke, with the most common involvement of splenium. Its clinical manifestations are mostly nonspecific, and a few may be manifested as disconnection syndrome. The etiology is mostly LAA, and the overall prognosis of such patients is good, and the poor prognosis may be related to the combination of multiple risk factors and the wide range of infarcts.