Copper(II), nickel(II) and zinc(II) complexes of both N-terminally acetylated and free tetrapeptides modeling the sequences at H96 (GTHS) and H111 (MKHM) sites of prion protein have been studied by potentiometric and various spectroscopic (UV-Vis, CD, EPR and NMR) techniques. Complex formation processes of the two tetrapeptides are very similar but copper(II) ions have enhanced affinity to form complexes with the -MKHM- sequence, while the opposite trend was obtained for nickel(II). The selectivity of metal binding of peptides was supported by DFT calculations, too. Three octapeptides NH 2 -GTHSMKHM-NH 2 , NH 2 -MKHMGTHS-NH 2 and Ac-GTHSMKHM-NH 2 containing the previous tetrapeptide domains have also been synthesized and studied with the same metal ions. All octapeptides are able to bind two copper(II) or nickel(II) ions and the histidyl residues are the primary metal binding sites. In the case of the N-terminally free octapeptides the first metal ion is always bonded to the amino terminus of both peptides reflecting the outstanding thermodynamic stability of the albumin-like binding site. The presence of coordination isomers was, however, identified for the mononuclear species of Ac-GTHSMKHM-NH 2 with a preference for copper(II) and nickel(II) binding at MKHM and GTHS sites, respectively. These data suggest that the specific sequences of prion fragments are responsible for the metal ion selectivity. Mixed metal copper(II)-nickel(II) complexes are also formed with all peptides showing the same preferences for metal binding as it was obtained for the binary systems.