We reported previously that the blood clearance of injected mouse IgG2a was extremely rapid in many strains of nude and nu/+ mice. In an attempt to determine the cause of this phenomenon, the levels of endogenous IgG2a in the blood of these mice was assayed. It was found that the serum level of IgG2a was extremely low in many of these mice, below 50 microg/ml, which is 20-100 times lower than the expected normal value. Great heterogeneity between individual mice was observed in their blood level of IgG2a, and there was an excellent correlation between low blood IgG2a levels and rapid clearance of injected IgG2a. Thus, the blood IgG2a levels are so low that a novel, previously undescribed effect occurs, namely the rapid clearance of small amounts of injected IgG2a. The clearance is due primarily to binding sites in the spleen and liver. The low level of endogenous IgG2a is not due to the lack of a thymus, since it occurs in nu/+ as well as nude mice, but can probably be attributed to the very clean environment in which these mice are raised. In assays of sera from approximately 50 mouse strains, low IgG2a levels were found in all nude colonies and also in some normal mouse strains. Some nude mice displayed relatively normal IgG2a clearance rates despite having low levels of endogenous IgG2a. In repeated bleedings of individual mice, IgG2a levels were found to fluctuate greatly. A similar clearance effect was observed with a human IgG1 Ab injected into mice. This rapid clearance of injected IgG, of certain subclasses, represents a practical problem for many experiments in which antibodies are used for diagnosis or therapy, and several methods of circumventing the problem are discussed.