We found significant amounts of enzymatic activity characteristic of the human neutrophil proteases, elastase and cathepsin G, associated with isolated amyloid fibrils from patients with five different types of systemic amyloidosis. Amyloid deposits in tissue sections from the patients with amyloid A, amyloid transthyretin and amyloid beta 2-microglobulin amyloidosis also stained positive with antiserum to elastase and cathepsin G. Elastase and cathepsin G, found in the azurophilic granules of the neutrophil and, to a lesser extent, the monocyte, may become associated with amyloid precursor proteins before or during the formation of amyloid fibrils. This may occur in an extracellular inflammatory microenvironment or in a phagolysosome and play a role in the formation of the fibrils.