Background:Sickle cell disease (SCD) is an autosomal recessive hemolytic disorder; its cerebrovascular complications include silent cerebral ischemia, infarct, and brain atrophy. Conventional magnetic resonance imaging (MRI) often underestimates the extent of injury. Diffusion tensor imaging (DTI) can demonstrate and quantify microstructural brain changes in SCD cases having normal routine MRI.Objective:To identify various neurological abnormalities in asymptomatic sickle cell patients using routine MRI and to evaluate the microstructure of various regions of the brain using DTI.Materials and Methods:A prospective, randomized case–control study was conducted over a period of 2 years. A total of 58 cases of SCD and 56 age- and sex-matched controls were included. Routine MRI and DTI were performed in both the groups following a standard protocol. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated in certain pre-defined regions. Primary data were analyzed using MS excel version 17. Analysis of variance test was performed and statistical significance was set at P < 0.05.Results:Thirty regions of interest with 60 variables were included in the final analysis. Patients with SCD showed statistically significant reduced FA values, increased ADC values, or both, clustered in several brain areas, including pons, cerebral peduncle, corpus callosum, frontal, temporal, parietal white matter, centrum semiovale, periventricular areas, basal ganglia, and left thalamus (P < 0.05).Conclusion:DTI is a promising method for characterizing microstructural changes, when conventional MRI is normal.