According to the amyloid cascade hypothesis, amyloid-β peptides (Aβ) play a causative role in Alzheimer's disease (AD), of which oligomeric forms are proposed to be the most neurotoxic by provoking oxidative stress. Copper ions seem to play an important role as they are bound to Aβ in amyloid plaques, a hallmark of AD. Moreover, Cu-Aβ complexes are able to catalyze the production of hydrogen peroxide and hydroxyl radicals, and oligomeric Cu-Aβ was reported to be more reactive. The flexibility of the unstructured Aβ peptide leads to the formation of a multitude of different forms of both Cu(I) and Cu(II) complexes. This raised the question of the structure-function relationship. We address this question for the biologically relevant Fenton-type reaction. Computational models for the Cu-Aβ complex in monomeric and dimeric forms were built, and their redox behavior was analyzed together with their reactivity with peroxide. A set of 16 configurations of Cu-Aβ was studied and the configurations were classified into 3 groups: (A) configurations that evolve into a linearly bound and nonreactive Cu(I) coordination; (B) reactive configurations without large reorganization between the two Cu redox states; and (C) reactive configurations with an open structure in the Cu(I)-Aβ coordination, which have high water accessibility to Cu. All the structures that showed high reactivity with H2O2 (to form HO(•)) fall into class C. This means that within all the possible configurations, only some pools are able to produce efficiently the deleterious HO(•), while the other pools are more inert. The characteristics of highly reactive configurations consist of a N-Cu(I)-N coordination with an angle far from 180° and high water crowding at the open side. This allows the side-on entrance of H2O2 and its cleavage to form a hydroxyl radical. Interestingly, the reactive Cu(I)-Aβ states originated mostly from the dimeric starting models, in agreement with the higher reactivity of oligomers. Our study gives a rationale for the Fenton-type reactivity of Cu-Aβ and how dimeric Cu-Aβ could lead to a higher reactivity. This opens a new therapeutic angle of attack against Cu-Aβ-based reactive oxygen species production.