Complement components, their activation and the generation of C3a and C5a peptides were studied in human lymph used as a model of tissue fluid. Both, classical and alternative pathways could be activated by suitable agents such as immune aggregates or zymosan. C3 activation and C3a formation were marked while only 10-15% of the anyway low amount of C5 were converted during complement activation, yielding very low concentrations of C5a. Carboxypeptidase N activity was present in lymph and converted the peptides to their less (C5a) or not at all (C3a) active desArg derivatives. Contact activation of Hageman factor and kallikrein enhanced activation of the classical pathway up to C3 conversion. The search for additional processes apt to create efficient concentrations of C5a (desArg) in lymph led to the discovery that the presence of leukocytes in lymph greatly increases the release of C5a activity upon complement activation. This suggests a physiological role of leukocytes resident in tissues for the induction of inflammatory reactions.