© 2019 Society of Biological Psychiatry Background: Schizophrenia is associated with progressive white matter changes, but it is unclear whether antipsychotic medications contribute to these. Our objective was to characterize effects of short-term treatment with risperidone on white matter diffusion indices. Methods: We recruited 42 patients with schizophrenia (30 never treated and 12 currently untreated)and 42 matched healthy control subjects in this prospective case-control neuroimaging study. Patients received a 6-week trial of risperidone. Using diffusion tensor imaging, we assessed microstructural (fractional anisotropy, mean diffusivity, and radial diffusivity)and macrostructural (radial fiber trophy)white matter integrity deficits in unmedicated patients compared with control subjects and change in white matter integrity in patients before and after antipsychotic treatment (mean risperidone dose at end point was 3.73 ± 1.72 mg). Results: At baseline, fractional anisotropy was decreased in the left medial temporal white matter (cluster extent: 123 voxels; Montreal Neurological Institute peak coordinates: x = −51, y = −44, z = −7; α <.05), and mean diffusivity was increased in the fusiform/lingual gyrus white matter extending to the hippocampal part of the cingulum (cluster extent: 185 voxels; peak coordinates: x = −27, y = −49, z = 2; α <.04)in patients compared with control subjects. Radial diffusivity and macrostructure were not abnormal. None of the diffusion indices showed a significant change after 6 weeks of treatment with both voxelwise and whole-brain white matter analyses. Conclusions: We demonstrate microstructural white matter integrity abnormalities in the absence of macrostructural impairment in unmedicated patients with primarily early-stage schizophrenia. In our data, we found no significant white matter changes after short-term treatment with risperidone.