Objective: To discuss the clinical features, imaging appearances and etiologies of corpus callosum lesions with magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) high signals. Methods: A retrospective study was carried out to analyze the etiologic, clinical and neuroimaging data of 48 patients hospitalized from 2015 to 2018, suffering from callosum lesions with DWI high signals. Results: Among the 48 patients with callosum lesions and DWI high signals, 35 suffered from acute cerebral infarction; 6 suffered from reversible splenial lesion syndrome (RESLES); 4 suffered from callosal tumor; 2 suffered from demyelinating diseases of the central nervous system and 1 chronic alcoholic encephalopathy. The primary cause for acute cerebral infarction was large artery atherosclerosis. The main causes for RESLES were infection and patients usually suffered from limb weakness, slurred speech, consciousness disorder, alien hand syndrome, dizziness, headaches, memory loss, and epileptic attack. Thirty-three patients (68.8%) had other intracranial lesions apart from callosum lesions. The lesions of RESLES patients were located symmetrically in splenium of corpus callosum, and no other intracranial lesions were observed. The genua of corpus callosum were the most commonly involved sites and single site involvement was most commonly found. Fourteen cases (29.2%) had symmetrical lesions. Conclusion: The most common etiology for callosum lesions with DWI high signal is acute cerebral infarction and the pathogenesis is still atherosclerosis, while demyelinating diseases of the central nervous system, RESLES, tumor and alcoholism could also be the causes. The lesions of RESLES patients are located only in splenium of corpus callosum while other intracranial lesions are observed in patients with acute cerebral infarction, demyelinating diseases of the central nervous system and tumors. Clinical manifestations of RESLES patients are varied.