Amyloid-β protein (Aβ) has been implicated in the pathogenesis of Alzheimer’s disease (AD) because of its neurotoxicity and its ability to trigger a local inflammatory response. In the present study using truncated Aβ peptides, we identified the region between residues 1 and 11 as critical for the activation of the contact system in vitro through an ionic interaction of Aβ with factor XII and/or kallikrein. Concomitant incubation of a small cationic peptide (lysine₄) with Aβ abrogated its ability to trigger the cleavage of high molecular weight kininogen, indicating that Aβ’s activity can be blocked by an inhibitory peptide. These findings could be clinically important, since there is evidence that the contact system is activated in AD brain. Thus, prevention of contact system activation, beside diminishing the recruitment of glial cells and microvascular permeability, can also decrease the activation of complement system and the release of IL6, both factors being considered to play an important role in the inflammatory reactions in AD brain.