Increased volume and density of the skull makes computed tomography differentiation of gray and white matter (GM and WM, respectively) more difficult. The purpose of this investigation was to study the effects of skull volume and bone density on GM and WM differentiation. A total of 21 patients with thick skulls and 22 controls were included in this study. Three consecutive slices from the computed tomography scan were analyzed. The basal ganglia had to be visualized on at least 1 slice. Calvarial volume measurement, mean pixel value in each slice, and Hounsfield unit difference between WM and GM, were compared between the thick-skulled and control groups. The mean bone volume of each slice in the thick-skulled group was 55.7, 54.3, and 56 mL, whereas the mean volume of each slice in the normal group was 39.3, 38.5, and 39.9 mL (P < 0.001). In our series, patients with thick skulls had 41% more bone volume than the normal group. The mean skull pixel value in each slice was 935.9 in patients with thick skulls and 987 in patients in the normal group. There was no difference between right and left sides of the same group of patients. Patients with larger volumes of skull have significant decrease in the Hounsfield unit of the GM and WM compared with the control group. As a result, diagnosing any low-contrast brain abnormality including early/subtle infarction in subjects with a thicker calvarium may be more difficult.