PURPOSE To evaluate the effects of drift in scanner hardware and inter-scanner variability on global and regional brain volume changes using longitudinal data obtained on two scanners of the exact same model. MATERIALS AND METHODS A total of 208 subjects (70 females and 138 males, mean age = 56.5 ± 10.1 years) were scanned twice, at an interval of approximately 2 years (mean interval = 1.9 ± 0.15 years), using two 3.0 Tesla (T) scanners of the exact same model. The subjects were divided into four groups according to the combination of scanners used. The effects of scanner drift and inter-scanner variability on global and regional brain volume changes were evaluated using voxel-based morphometry (VBM) and structural image evaluation using normalization of atrophy (SIENA). RESULTS The mean whole brain volume calculated using VBM increased by 17.2 ± 29.3 mL, and the changes were significantly different between groups. The mean percentage brain volume change (PBVC) calculated using SIENA was -0.46 ± 0.71 %, and did not differ between groups. VBM showed several regions with a significant increase or decrease in volume; however, SIENA showed that edge displacement values were negative in most regions. CONCLUSION Even with scanners of the exact same model, scanner drift, and inter-scanner variability can cancel out actual longitudinal brain volume change. SIENA, which corrects for differences in imaging geometry using the outer skull surface for both time points, can reduce the effects of scanner drift and inter-scanner variability on longitudinal morphometric results.