Deposition of β-amyloid (Aβ) peptides in the brain is an early and invariant feature of all forms of Alzheimer's disease. As with any secreted protein, the extracellular concentration of Aβ is determined not only by its production but also by its catabolism. A major focus of Alzheimer's research has been the elucidation of the mechanisms responsible for the generation of Aβ. Much less, however, is known about the mechanisms responsible for Aβ removal in the brain. In this report, we describe the identification of endothelin-converting enzyme-1 (ECE-1) as a novel Aβ-degrading enzyme. We show that treatment of endogenous ECE-expressing cell lines with the metalloprotease inhibitor phosphoramidon causes a 2–3-fold elevation in extracellular Aβ concentration that appears to be due to inhibition of intracellular Aβ degradation. Furthermore, we show that overexpression of ECE-1 in Chinese hamster ovary cells, which lack endogenous ECE activity, reduces extracellular Aβ concentration by up to 90% and that this effect is completely reversed by treatment of the cells with phosphoramidon. Finally, we show that recombinant soluble ECE-1 is capable of hydrolyzing synthetic Aβ40 and Aβ42 in vitro at multiple sites.