Purpose: To investigate the relationship between clinical stages and apparent diffusion coefficient (ADC) changes in the brain of patients with subacute sclerosing panencephalitis (SSPE).Materials and Methods: A total of 18 patients with stage II (N = 11) and III (N = 7) SSPE and 11 age‐matched controls underwent routine MRI and diffusion‐weighted imaging (DWI). The ADC values were automatically calculated. Seven distinct neuroanatomic structures (frontal, parieto‐occipital, and cerebellar white matter; deep white matter; thalamus; basal ganglia; and brainstem) were selected for analysis in the patient and control groups.Results: Hyperintensities in the periventricular and subcortical white matters on T2‐weighted images and ADC maps were detected in 63.6% of patients with stage II and in all patients with stage III. There were significant differences between stage II and III patients and also between patients and control group in ADC values that obtained from all locations. The highest mean ADC values were calculated in stage III patients. Although MRI and DWI findings were normal in four patients with stage II disease, ADC values were significantly increased when compared with controls.Conclusion: The stage of disorder may be independent of DWI appearance during the early stage (stages I and II), even though the brain is affected. Therefore, DWI and ADC values supplemental to routine MRI should also be utilized for lesion detection and definition to enhance diagnostic accuracy in patients with SSPE. J. Magn. Reson. Imaging 2006.