This study was designed to evaluate a potentially important source of error in T2-hyperintense lesion measurement unique to longitudinal multiple sclerosis treatment trials that would not be detected by the standard intraobserver and interobserver error analyses. The effect of this "error of serial studies" was tested by using the standard-of-reference manual-outlining approach and a modified bi-feature space (statistical) approach applied to a database of five consecutive patients. To simulate the conditions of a longitudinal treatment trial, each patient had immediate repeat MR studies of the brain with imperfect head repositioning. The study hypothesis was confirmed that with an improved quantitative methodology, the "error of serial studies" (interseries error) would exceed the intraobserver error.