The authors investigated whether identification of corpus callosal (CC) involvement might increase the specificity of magnetic resonance (MR) imaging in differentiating multiple sclerosis (MS) from other periventricular white matter diseases (PWDs). They prospectively evaluated 42 patients with MS and 127 control patients with other PWDs. Ninety-three percent of the MS patients demonstrated confluent and/or focal lesions involving the callosal-septal interface (CSI). These lesions characteristically involved the inferior aspect of the callosum and radiated from the ventricular surface into the overlying callosum. CSI lesions were optimally demonstrated on sagittal long repetition time (TR)/short echo time (TE) images and frequently (45% of cases) went undetected on axial images. Only 2.4% of the control patients had lesions of the CC. The authors conclude that midsagittal long TR/short TE images are highly sensitive and specific for MS and that callosal involvement in MS is more common than previously reported.