Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that affects approximately 3 - 8 people in 100,000 individuals worldwide. HD is caused by a mutation in the HTT gene, which codes for the protein huntingtin (HTT), consisting of an expansion of 35 CAG repeats in the exon 1 of the gene and resulting in the elongated polyglutamine (polyQ) stretch at the N-terminal fragment of the protein HTT. Individuals who suffer from HD develop severe motor, cognitive and psychiatric impairments, which primarily manifest in adulthood. The onset of the disease is usually inversely proportional to the CAG repeat expansion, however, HD comes with a high variability of symptoms. HD is also associated with the expression of the mutated HTT (mHTT) protein. The mHTT protein adopts a pathogenic conformation, which accumulates in small and/or large cytotoxic aggregates. Although these events are suspected to contribute to neurodegeneration, the exact mechanisms underlying the pathophysiological pathways leading to disease onset and neuronal death are still under investigation. A growing body of evidence suggests that mHTT possesses prion-like capacities – the capacity to spread between cells and seed disease – a phenomenon associated with other proteins such as amyloid, tau and a-synuclein, all involved in various neurodegenerative diseases. We hypothesized that mHTT propagates in a non-autonomous manner and behaves in a prion-like fashion to influence the onset and severity of HD. To address this, exogenous synthetic mHTT fibrils were administered to several cell lines and to mice of different genetic backgrounds. Following an incubation period, the effects of mHTT fibrils on cellular viability, animal behavior and neuropathological features were examined. We observed that mHTT fibrils provoked cell death and morphological changes in cultured cells, induced transient HD-related behavioral phenotypes in healthy mice and exacerbated motor, anxiety-like and cognitive deficits in an HD mouse model. Our study suggests that extracellular mHTT can propagate between cellular elements and once uptaken, trigger pathological changes. In light of these observations, we believe that extracellular mHTT could represent an appealing target for future therapeutic strategies. Current disease-modifying treatments tested in the clinic are designed to target the HTT gene to decrease the expression of the protein, overlooking the mHTT load outside of the cell boundaries and/or which has accumulated in the system prior to the application of gene silencing/editing. Hence, a combinational therapy addressing both the intracellular and extracellular expression of mHTT could serve as a more global treatment of HD.