White matter microstructural abnormalities in patients with classic trigeminal neuralgia (TN) have been observed. However, the impact of classic TN in both hemispheres, the difference and extent of alterations in bilateral hemispheres, and the relationship between the impaired area and pain conduction are not fully understood. The purpose of this study was to investigate brain microstructural alterations and compare the bilateral hemispheres in patients with unilateral classic TN, as well as to explore their clinical implications.The authors performed a cross-sectional study of 36 patients with left classic TN (TN group; age 40-66 years) and 36 healthy controls (HC group; age 40-66 years). Diffusion kurtosis imaging (DKI; b-values = 0, 1250, and 2500 sec/mm2) was performed in all patients using a 3T MRI scanner. The FMRIB Software Library with tract-based spatial statistics was used to analyze intergroup differences in both hemispheres. Atlas-based region of interest analysis was conducted in fiber tracts and gray matter structures.Decreased fractional anisotropy (FA) and increased mean diffusivity in 2.70% and 5.34% of white matter regions, such as the corona radiata, corpus callosum, internal capsule, superior longitudinal fasciculus, and cingulum, were detected in the TN group compared with the HC group (p < 0.05, family-wise error correction). Reduced mean kurtosis (MK), axial kurtosis, and radial kurtosis were detected in the bilateral thalamus in TN patients. The FA and MK values decreased asymmetrically in both cerebral hemispheres. Atlas-based region of interest analysis revealed more pronounced FA and MK reductions in the left thalamus and posterior corona radiata. There were negative associations of disease duration and pain intensity with the MK values in the thalamus, internal capsule, and superior corona radiata.The authors concluded that unilateral TN could have asymmetrical microstructural alterations in bilateral hemispheres, which might be due to the compromised fiber tract integrity and abnormal neurons and synapses. The thalamus could be an important relay station in the pain conduction and modulation pathway and could have microstructural abnormalities in both the left and right sides. DKI could provide important information on the CNS pathophysiology of TN and assist in prognostic evaluation.