The β-amyloid peptide (Aβ) is a normal product of the proteolytic processing of its precursor (β-APP). Normally, it elicits a very low humoral immune response; however, the aggregation of monomeric Aβ to form fibrillar Aβ amyloid creates a neo-epitope, to which antibodies are generated. Rabbits were injected with fibrillar human Aβ_1-42, and the resultant antibodies were purified and their binding properties characterized. The antibodies bound to an epitope in the first eight residues of Aβ and required a free amino terminus. Additional residues did not affect the affinity of the epitope as long as the peptide was unaggregated; the antibody bound Aβ residues 1−8, 1−11, 1−16, 1−28, 1−40, and 1−42 with similar affinities. In contrast, the antibodies bound ∼1000-fold more tightly to fibrillar Aβ_1-42. Their enhanced affinity did not result from their bivalent nature:  monovalent Fab fragments exhibited a similar affinity for the fibrils. Nor did it result from the particulate nature of the epitope:  monomeric Aβ_1-16 immobilized on agarose and soluble Aβ_1-16 exhibited similar affinities for the antifibrillar antibodies. In addition, antibodies raised to four nonfibrillar peptides corresponding to internal Aβ sequences did not exhibit enhanced affinity for fibrillar Aβ_1-42. Antibodies directed to the C-terminus of Aβ bound poorly to fibrillar Aβ_1-42, which is consistent with models where the carboxyl terminus is buried in the interior of the fibril and the amino terminus is on the surface. When used as an immunohistochemical probe, the antifibrillar Aβ_1-42 IgG exhibited enhanced affinity for amyloid deposits in the cerebrovasculature. We hypothesize either that the antibodies recognize a specific conformation of the eight amino-terminal residues of Aβ, which is at least 1000-fold more favored in the fibril than in monomeric peptides, or that affinity maturation of the antibodies produces an additional binding site for the amino-terminal residues of an adjacent Aβ monomer. In vivo this specificity would direct the antibody primarily to fibrillar vascular amyloid deposits even in the presence of a large excess of monomeric Aβ or its precursor. This observation may explain the vascular meningeal inflammation that developed in Alzheimer's disease patients immunized with fibrillar Aβ. Passive immunization with an antibody directed to an epitope hidden in fibrillar Aβ and in the transmembrane region of APP might be a better choice in the search for an intervention to remove Aβ monomers without provoking an inflammatory response.