An extremely rapid blood clearance rate of murine IgG2a antibodies was found in all strains tested of outbred Swiss nu/nu mice, including mice from the major commercial suppliers. The clearance half-life was less than 5 h, in comparison to a 4-5-day half-life in BALB/c mice. Therefore, most of the IgG2a antibody injected i.v. in such mice is cleared before it can reach interstitial fluid, which interferes with immunotherapy and immunodetection experiments. Individual nude mice varied greatly in their IgG2a clearance rates, which hampered investigation of the phenomena. In our experience, approximately three-fourths of nude mice had a rapid or intermediate clearance rate, whereas the remainder had an approximately normal clearance rate. The clearance rate in nude mice was age-dependent, at least in some instances, in that a rapid clearance rate was observed at 2 months of age, whereas the same mice retested at 4 months of age had a normal clearance rate. Rapid clearance could be inhibited by increasing the dose injected: 100 µg/mouse resulted in a normal clearance rate, whereas 30 µg/mouse was insufficient to inhibit rapid clearance. The clearance rate of IgG2b antibodies was affected similarly to that of IgG2a, whereas the clearance rate of IgG1 and IgG3 was not affected. The Fc region of IgG2a was required in order for rapid clearance to occur. Biodistribution experiments demonstrated that rapid blood clearance was due, at least partially, to binding to the liver and spleen. To determine the genetic basis for rapid IgG2a clearance, approximately 20 inbred and outbred mouse strains were tested. Unexpectedly, nu/+ as well as nu/nu outbred Swiss mice displayed rapid clearance, whereas control +/+ mice did not, so this phenotype appears to be a dominant effect of the nu mutation. BALB/c nu/nu and nu/+ mice did not display rapid clearance, which may be due to expression of the Igh-1ⁿ gene, which codes for the IgG2a present in BALB/c mice and in the monoclonal antibodies used in these studies. In conclusion, this clearance effect must be considered in experiments involving murine IgG2a or IgG2b antibodies in outbred Swiss nude mice, except those in which high antibody doses of >0.1 mg/mouse are used. One method of circumventing this problem is to increase the antibody dose injected; a better but more long-range method is to develop strains of outbred nude mice that do have this characteristic.