Leukocyte lysosomes contain materials which interact with the complement system in at least two ways to generate C5-derived lysosomal enzyme-releasing activity (C5a). Firstly, a lysosomal protease is capable of cleaving purified C5 at neutral pH to yield a low molecular weight product which selectively releases lysosomal, but not cytoplasmic, enzymes from isologous, cytochalasin B-treated, human polymorphonuclear leukocytes. The activity of this enzyme is inhibited by EACA and by normal human serum. Secondly, in fresh serum, lysosomal lysates generate the active form of the C3 proactivator and produce nonimmune hemolysis of dithiothreitol-treated erythrocytes, presumably by activation of the alternate pathway. Therefore, C5a activity is generated in human serum treated with lysates of leukocyte lysosomes as a consequence of complement activation: lysosomal constituents further their own release in a positive feed-back loop.