Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson’s disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons. Display omitted •α-syn antibodies block uptake of misfolded α-syn seeds•α-syn antibodies inhibit cell-to-cell spread of α-syn pathology•α-syn antibody to misfolded α-syn reduces pathology spread in vivo•α-syn antibody to misfolded α-syn ameliorates neuron loss and motor dysfunction Parkinson’s disease is characterized by the accumulation of misfolded α-synuclein as Lewy bodies. Through the use of in vitro and in vivo models expressing normal levels of endogenous α-synuclein that were induced to develop Lewy pathology by α-synuclein fibrils, Tran et al. show that α-synuclein immunotherapy prevents accumulation of pathologic α-synuclein and ameliorates neuron loss/motor dysfunction linked to α-synuclein pathology in part by blocking entry of pathologic α-synuclein into neurons. Thus, these studies support the therapeutic potential of α-synuclein immunotherapy.