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 β₂‐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 β₂‐microglobulin. We compared the half‐lives of radiolabelled mouse IgG1 injected intravenously into β₂‐microglobulin^−/− mice and wild‐type or heterozygous siblings. The clearance of ¹²⁵I‐labelled IgG1 was strikingly more rapid in the mice lacking β₂‐microglobulin. β₂‐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 β₂‐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 β₂‐microglobulin‐deficient and wild‐type mice. We compared the half‐lives of the four subclasses of mouse IgG in β₂‐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 β₂‐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.