The fifth component of human complement, C5, was activated by non-enzymical, chemical treatment in either of two ways: 1) by oxidation with a hydroxyl radical (OH.) generating system consisting of H2O2, FeEDTA, and ascorbate, activation product called C5(H2O2); 2) by oxidation with chloramine T, activation product called C5(Cl-T). Evaluating earlier findings, completed by new results, both products were compared. Both products are C5-like in that they are capable of binding C6 and form the nucleus for the cytotoxic complex C5-9. Both differ from C5b, the natural activation product of C5, as they comprise the whole, uncleaved C5 protein, and do not immediately decay when not bound to C6. In both cases the treatment involves oxidation of methionine residues in the C5 protein. However, while chloramine T specifically attacks only methionine, oxidation by the OH. generating system involves other amino acid residues, in addition. This probably explains the lower yield of C5b-like activity after treatment with H2O2, and other quantitative differences between C5(H2O2) and C5(Cl-T). Whereas the generation of C5(H2O2) may be physiologically relevant, C5(Cl-T) may prove to be a suitable object for the study of changes in the C5 molecule essential for its activation.