The assessment of resting-state functional connectivity has become an important tool in studying brain disease mechanisms. Here we use magnetoencephalography to longitudinally evaluate functional connectivity changes in relation to clinical measures of disease progression in Parkinson's disease (PD). Using a source-space based approach with detailed anatomical mapping, functional connectivity was assessed for temporal, prefrontal and high order sensory association areas known to show neuropathological changes in early clinical disease stages. At baseline, early stage, untreated PD patients (n = 12) had lower parahippocampal and temporal delta band connectivity and higher temporal alpha1 band connectivity compared to controls. Longitudinal analyses over a 4-year period in a larger patient group (n = 43) revealed decreases in alpha1 and alpha2 band connectivity for multiple seed regions that were associated with motor or cognitive deterioration. In the earliest clinical stages of PD, delta and alpha1 band resting-state functional connectivity is altered in temporal cortical regions. With disease progression, a reversal of the initial changes in alpha1 and additional decreases in alpha2 band connectivity evolving in a more widespread cortical pattern. These changes in functional connectivity appear to reflect clinically relevant phenomena and therefore hold promise as a marker of disease progression, with potential predictive value for clinical outcome. © 2013 The Authors. Published by Elsevier Inc. All rights reserved.