Amyloid beta (Aβ) immunization of amyloid precursor protein (APP)-transgenic (tg) mice with human Aβ induces humoral immunity, however, the immune response to endogenous rodent Aβ is unknown. Fourteen-month J20 APP-tg mice and non-tg littermates were immunized subcutaneously followed by chronic intranasal boosting with human or rodent Aβ peptide and adjuvant LT(R192G). Rodent Aβ-immunized APP-tg mice had anti-rodent Aβ antibody levels of 257.8μg/ml and those immunized with human Aβ had anti-human Aβ antibodies of 120.8μg/ml. Non-tg littermates had anti-rodent and anti-human Aβ antibody concentrations of 98.8 and 231.1μg/ml, respectively. Inter-species cross-reactivity was minimal. Anti-human Aβ antibodies were predominately IgG1 and IgG2b, while anti-rodent Aβ antibodies were equally IgG1, IgG2a, and IgG2b. Anti-human Aβ antibodies recognized an epitope within human Aβ1–9. Anti-rodent Aβ antibodies did not stain Alzheimer’s disease (AD) plaques but bound some plaques in APP-tg mice. Splenocytes proliferated modestly to their respective antigen and secreted low levels of IL-2 and IFN-γ. Therefore, immunizing APP-tg and non-tg mice with rodent Aβ resulted in a species-specific humoral response with modest T cell reactivity.