The measurement errors associated with two techniques for brain atrophy assessment in multiple sclerosis (MS) were estimated. The measurement error of a semiautomated, nonnormalized technique with partial brain coverage was about twofold higher than that of a fully automated, normalized technique with full brain coverage (Structural Image Evaluation of Normalized Atrophy software [SIENA]). As shown by the analysis of data from a clinical trial of glatiramer acetate, the use of SIENA increases the study power to detect a treatment effect on brain volume changes in MS patients.