Immunoglobulin E (IgE) is catabolized at a greater rate than any of the other immunoglobulins. To determine if this is due to an additional pathway of catabolism operating partly in the extravascular compartment, metabolic studies of radioiodinated IgE along with the other four major immunoglobulins were performed in 26 patients with nonallergic diseases and in two normal volunteers. The data of IgE and IgG metabolism were analyzed first by using computer fitting to compartmental models with and without an extravascular catabolic pathway. It was found that the IgE data could be best fit to the former model, whereas the data of IgG metabolism could be best fit to the latter model. The data of IgE and other immunoglobulins were then analyzed with the method of Nosslin. This method provides an intercept value from plots of calculated values derived from the amount of radioiodinated immunoglobulin in the serum and radioiodide in the urine at different time points after injection of labeled immunoglobulin. If the intercept value is equal to 1, there is no extravascular catabolism. The mean intercept value of IgE was 0.68 ± 0.15, which was significantly less than 1 (p < 0.001); similarly, the mean intercept value of IgD was 0.80 ± 0.11, which was also significantly less than 1 (p < 0.01). In contrast, the mean intercept values of IgG, IgA, and IgM were 0.92 ± 0.05, 1.14 ± 0.12, and 1.20 ± 0.31, respectively, which were not significantly different from 1 (p > 0.01). The results indicate that there is definite extravascular catabolism of IgE and possible extravascular catabolism of IgD, whereas there was no significant extravascular catabolism of the other three major immunoglobulin classes (IgG, IgA, and IgM). It is reasonable to propose that this extravascular catabolism is part of a unique catabolic mechanism specific for IgE which is related to unique interactions of IgE with basophils and mast cells.