Focal lesions limited to the splenium of the corpus callosum are rare and little is known about their etiology. We describe three patients with systemic lupus erythematosus (SLE) that presented transient lesions of the corpus callosum. We reviewed three patients with SLE whose magnetic resonance imaging (MRI) results revealed focal lesions in the splenum of corpus callosum. The medical records, including clinical, serological, and treatment features, were reviewed to determine the etiology of these lesions. Of 115 patients who had MRI for research purposes, three patients with focal nonhemorrhagic lesions of the corpus callosum were identified. All patients had active SLE at the time of MRI. One patient had other findings on MRI, including cerebral venous thrombosis. On follow-up MRI, patients had an inactive disease and the corpus callosum lesions disappeared. A transient lesion in the splenium of corpus callosum seems to be a nonspecific endpoint of different disease processes leading to vasogenic edema. The complete and rapid reversibility in all cases with disease control is emphasized and any invasive diagnostic or therapeutic approach is discouraged.