Abstract Purpose To assess the clinical impact and incremental diagnostic value of ¹⁸F-fluorodeoxyglucose (FDG-PET) among memory clinic patients with uncertain diagnosis. Methods The study population consisted of 277 patients who, despite extensive baseline cognitive assessment, MRI, and CSF analyses, had an uncertain diagnosis of mild cognitive impairment (MCI) (n = 177) or dementia (n = 100). After baseline diagnosis, each patient underwent an FDG-PET, followed by a post-FDG-PET diagnosis formulation. We evaluated (i) the change in diagnosis (baseline vs. post-FDG-PET), (ii) the change in diagnostic accuracy when comparing each baseline and post-FDG-PET diagnosis to a long-term follow-up (3.6 ± 1.8 years) diagnosis used as reference, and (iii) comparative FDG-PET performance testing in MCI and dementia conditions. Results FDG-PET led to a change in diagnosis in 86 of 277 (31%) patients, in particular in 57 of 177 (32%) MCI and in 29 of 100 (29%) dementia patients. Diagnostic change was greater than two-fold in the sub-sample of cases with dementia “of unclear etiology” (change in diagnosis in 20 of 32 (63%) patients). In the dementia group, after results of FDG-PET, diagnostic accuracy improved from 77 to 90% in Alzheimer’s disease (AD) and from 85 to 94% in frontotemporal lobar degeneration (FTLD) patients (p < 0.01). FDG-PET performed better in dementia than in MCI (positive likelihood ratios >5 and < 5, respectively). Conclusion Within a selected clinical population, FDG-PET has a significant clinical impact, both in early and differential diagnosis of uncertain dementia. FDG-PET provides significant incremental value to detect AD and FTLD over a clinical diagnosis of uncertain dementia.