Cannabis use is associated with changes in brain structure and function; its neurotoxic effects are largely attributed to Δ<sup>9</sup>-tetrahydrocannabidiol. Whether such effects are present in patients with epilepsy exposed to a highly-purified cannabidiol isolate (CBD; Epidiolex®; Greenwich Biosciences, Inc.) has not been investigated to date. This preliminary study examines whether daily CBD dose of 15-25 mg/kg produces cerebral macrostructure changes and, if present, how they relate to changes in seizure frequency. Twenty-seven patients with treatment-resistant epilepsy were recruited from the University of Alabama at Birmingham CBD Program. Participants provided seizure frequency diaries (SF), completed the Chalfont Seizure Severity Scale (CSSS) and Adverse Events Profile (AEP), and underwent MRI before CBD (baseline) and after achieving a stable CBD dosage (on-CBD). We examined T1-weighted structural images for gray matter volume (GMV) and cortical thickness changes from baseline to on-CBD in 18 participants. Repeated measures t-tests confirmed decreases in SF [t(17) = 3.08, <i>p</i> = 0.0069], CSSS [t(17) = 5.77, <i>p</i> < 0.001], and AEP [t(17) = 3.04, <i>p</i> = 0.0074] between the two time-points. Voxel-level paired samples t-tests did not identify significant changes in GMV or cortical thickness between these two time-points. In conclusion, short-term exposure to highly purified CBD may not affect cortical macrostructure.