With the advent of new and more effective drugs for the treatment of Alzheimer's disease (AD), establishment of objective surrogate markers of disease progression has become an issue of high clinical relevance. In order to investigate the potential of volumetric magnetic resonance imaging (MRI) for monitoring disease progression, we investigated the progression rates of hippocampal and generalized brain atrophy in a group of AD patients with respect to rates of clinical deterioration. While AD, in comparison to healthy aging, was characterized by a rapid decline of hippocampal volumes, only a moderate decrease of whole brain volumes occurred, indicating that hippocampal atrophy was not merely a function of generalized brain atrophy. Progression of hippocampal atrophy, but not of whole brain atrophy, was significantly correlated with clinical deterioration. These findings indicate that progressive hippocampal volume reduction underlies clinical deterioration in AD and that the rate of hippocampal atrophy might be used as a morphometric index of disease progression in clinical drug trials. Drug Dev. Res. 56:51–56, 2002. © 2002 Wiley-Liss, Inc.