The β‐amyloid peptide (Aβ) is a normal proteolytic processing product of the amyloid precursor protein, which is constitutively expressed by many, if not most, cells. For reasons that are still unclear, Aβ is deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease (AD). The factor(s) responsible for the clearance of soluble Aβ from biological fluids or tissues are poorly understood. We now report that human α₂‐macroglobulin (α₂M), a major circulating endoproteinase inhibitor, which has recently been shown to be present in senile plaques in AD, binds ¹²⁵I‐Aβ_(1–42) with high affinity (apparent dissociation constant of 3.8 × 10⁻¹⁰M). Approximately 1 mol of Aβ is bound per mole of α₂M. Both native and methylamine‐activated α₂M bind ¹²⁵I‐Aβ_(1–42). The binding of ¹²⁵I‐Aβ_(1–42) to α₂M is enhanced by micromolar concentrations of Zn²⁺ (but not Ca²⁺) and is inhibited by noniodinated Aβ_(1–42) and Aβ_(1–40) but not by the reverse peptide Aβ_(40‐1) or the cytokines interleukin 1β or interleukin 2. α₁‐Antichymotrypsin, another plaque‐associated protein, inhibits both the binding of ¹²⁵I‐Aβ_(1–42) to α₂M as well as the degradation of ¹²⁵I‐Aβ_(1–42) by proteinase‐activated α₂M. Moreover, the binding of ¹²⁵I‐Aβ_(1–42) to α₂M protects the peptide from proteolysis by exogenous trypsin. These data suggest that α₂M may function as a carrier protein for Aβ and could serve to either facilitate or impede clearance of Aβ from tissues such as the brain.