Sex difference is related to specific clinical features in PD patients over the disease course. To investigate the potential sex-difference effect on the spontaneous neuronal activity within the most reported resting-state networks in early untreated PD patients and its correlation with baseline and longitudinal clinical features. Fifty-six drug-naïve PD patients (30/26 male/female) and 30 (15/15 male/female) matched controls were enrolled in the study. Topological and spectral resting-state functional MRI features of the sensorimotor, dorsal and ventral attention, frontoparietal, and default-mode networks were analyzed for possible sex-difference effects in both PD patients and controls groups. Additionally, a region-of-interest analysis was performed to test for a sex effect on basal ganglia connectivity. Multivariate ordinal regression was used to investigate whether connectivity findings at baseline were predictors of motor impairment over a 2-year follow-up period. Compared to female PD patients and controls, male PD patients showed an abnormal spectral composition of the sensorimotor and dorsal attention networks in the slow-5 band. The region-of-interest analysis showed an increased connectivity within the basal ganglia in female PD patients compared to males. Functional sensorimotor connectivity changes at baseline showed to be an independent predictor of disease severity at 2-year follow-up. Our findings revealed the presence of a disease-related, sex-specific cortical and subcortical connectivity pattern within the sensorimotor network, in the early stage of PD. We hypothesize that these findings may be related to the presence of different sex-specific nigrostriatal dopaminergic pathways and might predict PD progression. © 2019 International Parkinson and Movement Disorder Society.