This paper reports an active decapeptide inhibitor (RR: RYYAAFFARR) of beta-amyloid (A beta(1-40)) aggregation. Traditional inhibitors target the hydrophobic core of A beta (A beta(16-20)) and were designed based on the single hydrophobic interaction. RR was designed to target an extended region (A beta(11-23)), which contains three important regions of A beta(1-40). RR exhibits stronger binding affinity for A beta(1-40) (K-D = 1.10 mu M) than the known beta-sheet breaker LPFFD (K-D = 156 mu M). Our study shows that RR inhibited the fibrillation of A beta(1-40) by nearly 75% at an equimolar concentration, and that a 1:4 ratio of A beta(1-40) RR almost completely inhibited fibrillation. The interaction mechanism was also investigated by changing the ionic strength or the structure of RR The results revealed that RR binds to A beta(1-40) because of its strong affinity for A beta(11-23), which is mainly driven by hydrophobic and electrostatic interactions and hydrogen bonding.