Rats and guinea pigs were depleted of complement (C') by treatment with heat aggregated human gamma-globulin (agg HGG), zymosan, anti-beta1C globulin, and carrageenan. Although antigen and antibody were bound to vascular structures, Arthus reactions were inhibited. This inhibition was characterized by the lack of C' binding to walls of vessels, the lack of polymorphonuclear (PMN's) cellular infiltrates, and the lack of significant vascular damage. When the same animals were followed for several hours thereafter, levels of serum C' began to rise, C' was bound in tissues, PMN infiltrates appeared, and immunologic vasculitis developed. Blood counts, chemotaxis of PMN's induced by lysates of PMN granules, together with studies on motility and phagocytosis by PMN's obtained from C' depleted rats, failed to establish any abnormality in these cells which would account for inhibition of Arthus reactions. The specificity of C' depletion in terms of effects in the first four reacting components of guinea pig C' was studied. Treatment with agg HGG led to loss of activity in all components, whereas zymosan and anti-beta1C globulin predominately affected the third component (C'3c). Carrageenan mainly affected the first two reacting components of C'. Thus, the availability of the 3c component, or a subsequently reacting component, correlated with the attraction of PMN's to immune reactants in vivo. Various antibodies with different C' fixing capacities in vitro were tested for their ability to induce immunologic vasculitis in normal animals. In rats, only those antibodies which fixed C' in vitro possessed biological activity, whereas in guinea pigs, all antibodies tested, regardless of C' fixation in vitro, induced Arthus reactions. For a given antibody in rats the vasculitis-inducing property was reflected in its ability to bind C' in vascular structures. Rats depleted of circulating PMN's by specific antibody were tested for Arthus activity. Although concentrations of immune reactants and C' were readily detected in vascular structures, no PMN infiltration occurred and significant vascular damage was averted.