A ccumulation and aggregation of amyloid β peptide 1–42 (Aβ₄₂) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of Aβ₄₂ versus Aβ₄₀ or total Aβ is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-Aβ₄₂ mAb, an anti-Aβ₄₀ mAb, and multiple Aβ_1–16 mAbs. We established in vivo binding selectivity of the anti-Aβ₄₂ and anti-Aβ₄₀ mAbs using novel TgBRI-Aβ mice. We then conducted a prevention study in which the anti-Aβ mAbs were administered to young Tg2576 mice, which have no significant Aβ deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting Aβ deposits. Anti-Aβ₄₂, anti-Aβ₄₀, and anti-Aβ_1–16 mAbs attenuated plaque deposition in the prevention study. In contrast, anti-Aβ₄₂ and anti-Aβ₄₀ mAbs were less effective in attenuating Aβ deposition in the therapeutic studies and were not effective in clearing diffuse plaques following direct injection into the cortex. These data suggest that selective targeting of Aβ₄₂ or Aβ₄₀ may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting.