Neurofilament light chain (NFL) has been recently introduced as a biomarker of early dementia. 18-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a proxy for regional hypometabolism in Alzheimer disease (AD). Globally normalized 18F-FDG-PET values and levels of NFL and tau were obtained from 149 patients with mild cognitive impairment (MCI) from the baseline cohort of the Alzheimer's Disease Neuroimaging Initiative database. We adopted a stepwise partial correlation model using plasma NFL, plasma tau, CSF NFL, and regional cerebral metabolic rate of glucose (CMRGlc) as main variables, and age, sex, and Alzheimer's Disease Rating Scale (ADAS) as covariates. Significant regions were entered into a stepwise multiple regression analysis to investigate the independent correlation of each biomarker to baseline regional CMRGlc and its progression in patients with MCI. Higher baseline CSF NFL levels correlated with hypometabolism in bilateral precuneal and posterior cingulate cortex. After correction for age, sex, and ADAS score, plasma NFL levels correlated with hypometabolism in bilateral parahippocampal and middle temporal gyri. Cortical hypometabolism in bilateral parahippocampal gyri and right fusiform and middle temporal gyri was independently predicted by higher baseline plasma NFL levels in a multiple regression model. Plasma NFL promises to be an early biomarker of cortical hypometabolism in MCI and for MCI progression to AD.