This paper reports a series of heterodivalent linked macrocyclic beta-sheets 6 that are not only far more active against amyloid-beta (A beta) aggregation than their monovalent components 1a and 1b but also are dramatically more active than their homodivalent counterparts 4 and 5. The macrocyclic beta-sheet components 1a and 1b comprise pentapeptides derived from the N- and C-terminal regions of A beta and molecular template and turn units that enforce a beta-sheet structure and block aggregation. Thioflavin T fluorescence assays show that heterodivalent linked macrocyclic beta-sheets 6 delay A beta(1-40) aggregation 6-8-fold at equimolar concentrations and substantially delay aggregation at substoichiometric concentrations, while homodivalent linked macrocyclic beta-sheets 4 and 5 and monovalent macrocyclic beta-sheets 1a and 1b only exhibit more modest effects at equimolar or greater concentrations. A model to explain these observations is proposed, in which the inhibitors bind to and stabilize the early beta-structured A beta oligomers and thus delay aggregation. In this model, heterodivalent linked macrocyclic beta-sheets 6 bind to the beta-structured oligomers more strongly, because N-terminal-derived component 1a can bind to the N-terminal-based core of the beta-structured oligomers, while the C-terminal-derived component 1b can achieve additional interactions with the C-terminal region of A beta. The enhanced activity of the heterodivalent compounds suggests that polyvalent inhibitors that can target multiple regions of amyloidogenic peptides and proteins are better than those that only target a single region.