It has been demonstrated that immunization of transgenic mouse models of Alzheimer’s disease (AD) with amyloid-β1–42 peptide (Aβ1–42) results in prevention of Ah plaque formation and amelioration of established plaques in the brain. As the response of the T lymphocyte helper (Th) arm of the immune response had not yet been investigated after Aβ immunization, we i.p. immunized C57BL/6 mice with Aβ1–42, Aβ1–40, or phosphate-buffered saline (PBS), and examined markers of Th1 and Th2 immune responses in spleen and in splenocytes from these mice. Spleens from Aβ1–42-immunized mice demonstrated decreased interleukin-12 receptor beta chain expression compared to mice immunized with Aβ1–40 or PBS. Consistently, following stimulation with concanavalin A or anti-CD3 antibody, primary splenocytes from Aβ1–42-immunized mice demonstrated elevated secretion of interleukin-4 and interleukin-10, and decreased levels of interferon-γ. To validate this Th1→Th2 shift in a transgenic mouse model of AD, we immunized Tg APPsw mice (line 2576) with Aβ1–42 and found decreased Th1 (interleukin-2 and interferon-γ) and elevated Th2 (interleukin-4 and interleukin-10) cytokines in their stimulated primary splenocytes. Interferon-γ was markedly reduced and interleukin-10 was increased in blood plasma from these mice, effects that were associated with dramatically mitigated Aβ deposition after Aβ1–42 immunization. Taken together, these results show enhanced Th2 and down-regulated Th1 immunity following immune challenge with Aβ1–42.