The relationship between certain physicochemical properties of circulating immune complexes and their ability to localize in vessel walls during a state of increased permeability was studied. The ability to become deposited was related to the large size of complexes, rather than to their net charge or to a specific affinity between complexes and structures of vessel walls. Soluble complexes with sedimentation rates greater than 19S were capable of being entrapped along the vessel wall membranes, while complexes smaller than this were not. These large complexes were removed rapidly from the circulation, while smaller complexes persisted. Minimal levels of total complexes in the circulation necessary for detectable vascular localization were found to be as low as 15 microg antibody N/ml plasma. In experimental serum sickness, a disease known to be induced by circulating immune complexes, the development of vascular and glomerular lesions occurred almost exclusively in rabbits having large (greater than 19S) circulating immune complexes. Animals with smaller complexes did not show deposition of complexes in glomeruli or development of glomerulonephritis. Their incidence of vasculitis was markedly reduced.