In this paper, we validate the brain boundary shift integral (BBSI) as a measure of brain atrophy and demonstrate its application in Alzheimer's disease (AD). Nineteen normal subjects and nine patients with AD underwent serial three-dimensional MRI (6- to 30-month scan intervals). Repeat studies were registered to the baseline studies. The accuracy of the BBSI was assessed by comparison with simulated atrophy and with segmentation; it was also tested for reproducibility, linearity, and its ability to discriminate patients with AD from healthy controls. The BBSI correlated closely with simulated volumes of atrophy (r = 1.000). The mean absolute difference between repeat measures was 1.51 ml or .13% of mean brain volume. Rates of atrophy from all 18 AD scan pairs were widely separated from those of all 31 control pairs. In matched subgroups, the mean (SD) annual rate of brain atrophy in nine controls was .24% (.32%), compared with 2.78% (.92%) in nine patients with AD. We conclude that the BBSI is a linear and highly reproducible measure of atrophy with potential uses in the early diagnosis and measurement of progression in Alzheimer's disease.