PurposeDementia with Lewy bodies (DLB) is characterized by a wide clinical and biological heterogeneity, with sex differences reported in both clinical and pathologically confirmed DLB cohorts. No research evidence is available on sex differences regarding molecular neurotransmission. This study aimed to assess whether sex can influence neurotransmitter systems in patients with probable DLB (pDLB).MethodsWe included 123 pDLB patients (male/female: 77/46) and 78 control subjects (male/female: 34/44) for comparison, who underwent123I-FP-CIT SPECT imaging. We assessed sex differences in the dopaminergic activity of the nigrostriatal and mesolimbic systems using regional-based and voxel-wise analyses of123I-FP-CIT binding. We tested whether sex-specific binding alterations would also pertain to the serotoninergic and noradrenergic systems by applying spatial correlation analyses. We applied molecular connectivity analyses to assess potential sex differences in the dopaminergic pathways.ResultsWe found comparable123I-FP-CIT binding decreases in the striatum for pDLB males and females compared to controls. However, pDLB females showed lower binding in the extrastriatal projections of the nigrostriatal and mesolimbic dopaminergic systems compared to pDLB males. According to the spatial correlation analysis, sex-specific molecular alterations were also associated with serotonergic and noradrenergic systems. Nigrostriatal and mesolimbic systems’ connectivity was impaired in both groups, with males showing local alterations and females presenting long-distance disconnections between subcortical and cortical regions.ConclusionsSex-specific differences in123I-FP-CIT binding were found in our cohort, namely, a trend for lower123I-FP-CIT binding in females, significant in the presence of a pDLB diagnosis. pDLB females showed also different patterns of connectivity compared to males, mostly involving extrastriatal regions. The results suggest the presence of a sex-related regional vulnerability to alpha-synuclein pathology, possibly complicated also by the higher prevalence of Alzheimer’s disease co-pathology in females, as previously reported in pDLB populations.Supplementary informationThe online version contains supplementary material available at 10.1007/s00259-023-06132-4.