The mechanisms that regulate immunoglobulin G (IgG) catabolism are little understood. We have previously found unusually low IgG concentrations in sera of mice homozygous for a targeted disruption of the beta 2-microglobulin gene. We therefore investigated whether this might result, at least in part, from increased clearance of IgG from the systemic circulation in mice lacking beta 2-microglobulin. We compared the half-lives of radiolabelled mouse IgG1 injected intravenously into beta 2-microglobulin-/- mice and wild-type or heterozygous siblings. The clearance of 125I-labelled IgG1 was strikingly more rapid in the mice lacking beta 2-microglobulin. beta 2-microglobulin-/- mice lack functional molecules of the MHC class I-related Fc receptor, FcRn. Some mutations in mouse IgG1 that increase its clearance have recently been shown to prevent binding to FcRn in the gut. To determine whether the slower degradation of immunoglobulin in mice with beta 2-microglobulin correlated with the ability of the antibody to bind FcRn, we measured the clearance of chicken IgY, which does not bind this receptor. The 125I-labelled IgY was catabolized equally rapidly in beta 2-microglobulin-deficient and wild-type mice. We compared the half-lives of the four subclasses of mouse IgG in beta 2-microglobulin-/-, +/-, and +/+ mice to determine whether the difference we had noted for IgG1 was peculiar to this subclass. The 125I-labelled IgG of all subclasses, with the possible exception of IgG2b. was degraded more rapidly in the beta 2-microglobulin-deficient mice than in heterozygous or wild-type siblings. These data suggest that FcRn can protect IgG from degradation, and is therefore important in maintaining IgG levels in the circulation.