Prion protein (PrP) amyloid formation is a central feature of genetic and acquired prion diseases such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant CJD. The major component of GSS amyloid is a PrP fragment spanning residues ~82-146 which, when synthesized as a peptide, readily forms fibrils featuring GSS amyloid. The present study employed surface plasmon resonance (SPR) to characterize the binding events underlying PrP82-146 oligomerization at the first stages of fibrillization, according to evidence suggesting a pathogenic role of prefibrillar oligomers rather than mature amyloid fibrils. We followed in real-time the binding reactions occurring during short-term (sec) addition of PrP82-146 small oligomers (1-5mers, flowing species) onto soluble prefibrillar PrP82-146 aggregates immobilized on the sensor surface. SPR data confirmed very efficient aggregation/elongation, consistent with the hypothesis of nucleation-dependent polymerization process. Much lower binding was observed when PrP82-146 flowed onto the scrambled sequence of PrP82-146 or onto prefibrillar A42 aggregates. As previously found with A40, SPR data could be adequately fitted by equations modelling the “dock-and-lock” mechanism, in which the “locking” step is due to sequential conformational changes, each increasing the monomer’s affinity for the fibril until to condition of irreversible binding is reached. However, these conformational changes (i.e., the locking steps) appear to be faster and easier with PrP82-146 than with A40. Such differences suggest that PrP82-146 has a greater propensity to polymerize and greater stability of the aggregates.