© 2014 Wolters Kluwer Health, Inc. All rights reserved. Background: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). Methods: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aβ1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. Results: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. Conclusion: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.