Background: Conventional MRI provides important morphologic information regarding the brain and spinal cord involvement by demyelinating plaques. However, it is of almost no value in assessing the normal-appearing white matter which has been proved by multiple pathologic studies to be directly and indirectly involved in the process of multiple sclerosis. Diffusion-weighted imaging and diffusion tensor imaging MRI have been widely used in multiple researches as a better solution for studying the normal-appearing white matter. The purpose of this study was to evaluate the role of diffusion tensor imaging examination of the normal-appearing white matter of the brain and spinal cord in patients with multiple sclerosis and to determine the relationship between diffusion tensor imaging metrics and patient's clinical status. Results: The significant negative correlation found between expanded disability status scale score of secondary progressive MS patients and global (brain and spinal cord) average fractional anisotropy values in normal-appearing white matter and tracts (P = 0.000). Correlation between average apparent diffusion coefficient of corpus callosum tract and expanded disability status scale score revealed a significant positive correlation in RRMS (P = 0.001). While in secondary progressive MS, a significant negative correlation between fractional anisotropy average of the corpus callosum tract and expanded disability status scale score was noted (P = 0.015). Conclusion: There is a strong relationship between diffusion tensor imaging readings and clinical status of patients can be used to understand unexplained deterioration over disease course and also can be used when conventional MRI findings are equivocal. Corpus callosum affection in MS patients is intimately related to clinical status and its assessment should be done whenever possible.