SienaX and Siena are widely used and fully automated algorithms for measuring whole brain volume and volume change in cross-sectional and longitudinal MRI studies and are particularly useful in studies of brain atrophy. The reproducibility of the algorithms was assessed using the 3D T1 weighted MP-RAGE scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The back-to-back (BTB) MP-RAGE scans in the ADNI data set makes it a valuable benchmark against which to assess the performance of algorithms of measuring atrophy in the human brain with MRI scans. A total of 671 subjects were included for SienaX and 385 subjects for Siena. The annual percentage brain volume change (PBVC) rates were -0.65 ± 0.82%/year for the healthy controls, -1.15 ± 1.21%/year for mild cognitively impairment (MCI) and -1.84 ± 1.33%/year for AD, in line with previous findings. The median of the absolute value of the reproducibility of SienaX's normalized brain volume (NBV) was 0.96% while the 90th percentile was 5.11%. The reproducibility of Siena's PBVC had a median of 0.35% and a 90th percentile of 1.37%. While the median reproducibility for SienaX's NBV was in line with the values previously reported in the literature, the median reproducibility of Siena's PBVC was about twice that reported. Also, the 90th percentiles for both SienaX and Siena were about twice the size that would be expected for a Gaussian distribution. Because of the natural variation of the disease among patients over a year, a perfectly reproducible whole brain atrophy algorithm would reduce the estimated group size needed to detect a specified treatment effect by only 30% to 40% as compared to Siena's. © 2011 Elsevier Ireland Ltd.