Background: Magnetic resonance imaging (MRI) may show discrete splenium abnormalities; however, the implications of this radiologic finding are unclear. Objective: To describe causes, clinical presentations, and prognoses of midline splenium changes evident on MRI. Design: Retrospective case series. Setting: Teaching hospital. Patients: Medical records of 9 patients with MRI-noted splenium changes were studied; 60 additional published cases were accessed. Interventions: Sixty-nine cases were reviewed. Main Outcome Measures: Clinical and imaging findings, causes, and prognosis. Results: Confusion (35 patients), ataxia (25 patients), and recent seizure (23 patients) were common. Causes included alcohol use, infections, hypoglycemia, trauma, salt abnormalities, and seizure. Twenty-eight patients had complete resolution, 23 improved, and 1 died. Diffusion weighted imaging showed splenium abnormalities the best. Eleven of 12 patients showed decrease in apparent diffusion coefficient. Most improved clinically, as did their subsequent MRI studies. Conclusions: Midline splenium changes are commonly seen on MRI diffusion-weighted imaging sequences. Multiple causes can result in splenium changes. Physicians should evaluate for glucose and electrolyte abnormalities, seizure risk, ongoing infectious or parainfectious process, and traumatic causes.