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Background: The amnestic presentation of mild cognitive impairment (aMCI) represents the most common prodromal stage of Alzheimer's disease (AD) dementia. There is, however, some evidence of aMCI with typical amnestic syndrome but showing long-term clinical stability. The ability to predict stability or progression to dementia in the aMCI condition is important, particularly for the selection of candidates in clinical trials. We aimed to establish the role of in vivo biomarkers, as assessed by cerebrospinal fluid (CSF) measures and [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, in predicting prognosis in a large aMCI cohort. Methods: We conducted a retrospective study, including 142 aMCI subjects who had a long follow-up (4–19 years), baseline CSF data and [18F]FDG-PET scans individually assessed by validated voxel-based procedures, classifying subjects into either limbic-predominant or AD-like hypometabolism patterns. Results: The two aMCI cohorts were clinically comparable at baseline. At follow-up, the aMCI group with a limbic-predominant [18F]FDG-PET pattern showed clinical stability over a very long follow-up (8.20 ± 3.30 years), no decline in Mini-Mental State Examination score, and only 7% conversion to dementia. Conversely, the aMCI group with an AD-like [18F]FDG-PET pattern had a high rate of dementia progression (86%) over a shorter follow-up (6.47 ± 2.07 years). Individual [18F]FDG-PET hypometabolism patterns predicted stability or conversion with high accuracy (area under the curve = 0.89), sensitivity (0.90) and specificity (0.89). In the limbic-predominant aMCI cohort, CSF biomarkers showed large variability and no prognostic value. Conclusions: In a large series of clinically comparable subjects with aMCI at baseline, the specific [18F]FDG-PET limbic-predominant hypometabolism pattern was associated with clinical stability, making progression to AD very unlikely. The identificatio