It has been demonstrated that immunization of transgenic mouse models of Alzheimer's disease (AD) with amyloid-β_1–42 peptide (Aβ_1–42) results in amelioration of AD-like pathology, including reduced soluble and deposited β-amyloid and decreased cognitive impairment. Based on the proposed importance of immunoglobulin G (IgG) anti-Aβ antibodies (Abs) in these effects, we sought to characterize these Abs in splenocytes from mice immunized with Aβ_1–42. Data show that a more aggregated preparation of Aβ_1–42 gives a robust IgG anti-Aβ Ab response, while these Abs are almost undetectable when a less aggregated preparation of Aβ_1–42 is used as the immunogen. Importantly, IgG anti-Aβ Ab production is detected after just 12 weeks of Aβ_1–42 treatment. Analysis of anti-Aβ Ab IgG isotypes reveals that the majority of these Abs are IgG1, with significantly fewer Abs of the IgG2a or IgG2b isotypes (IgG1>IgG2a>IgG2b), suggesting a T lymphocyte helper type II response after Aβ_1–42 immunization. To determine the epitope of Aβ recognized by IgG anti-Aβ Abs, intact Aβ and Aβ peptide fragments were analyzed for their ability to bind these Abs. Data show that these Abs specifically recognize an amino-terminal epitope of Aβ between amino acids one and twelve, with higher affinity for a more soluble preparation of Aβ_1–42. These data further indicate the immunogenic potential of Aβ_1–42 and offer insight into the nature of the IgG anti-Aβ Ab response.