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We investigate the interaction of hemin with four fragments of prion protein (PrP) containing from one to four histidines (PrP_106–114, PrP_95–114, PrP_84–114, PrP_76–114) for its potential relevance to prion diseases and possibly traumatic brain injury. The binding properties of hemin-PrP complexes have been evaluated by UV–visible spectrophotometric titration. PrP peptides form a 1:1 adduct with hemin with affinity that increases with the number of histidines and length of the peptide; the following log K₁ binding constants have been calculated: 6.48 for PrP_76–114, 6.1 for PrP_84–114, 4.80 for PrP_95–114, whereas for PrP_106–114, the interaction is too weak to allow a reliable binding constant calculation. These constants are similar to that of amyloid-β (Aβ) for hemin, and similarly to hemin-Aβ, PrP peptides tend to form a six-coordinated low-spin complex. However, the concomitant aggregation of PrP induced by hemin prevents calculation of the K₂ binding constant. The turbidimetry analysis of [hemin-PrP_76–114] shows that, once aggregated, this complex is scarcely soluble and undergoes precipitation. Finally, a detailed study of the peroxidase-like activity of [hemin-(PrP)] shows a moderate increase of the reactivity with respect to free hemin, but considering the activity over long time, as for neurodegenerative pathologies, it might contribute to neuronal oxidative stress.