Abstract The titer of anti-A and anti-B isoagglutinins were determined in the sera of 100 patients with diseases affecting γ-globulin levels. The values for isoagglutinins, known to be chiefly 18S γ-globulins, were correlated with the total γ-globulin levels and determinations of 6.6S and 18S globulin obtained by electrophoresis and ultracentrifugation. Low isoagglutinin levels were frequently observed secondary to protein loss (exudative enteropathy and nephrosis) and in malignant disease of plasma cells and lymphocytes (multiple myeloma, Waldenstrom's macroglobulinemia, and chronic lymphocytic leukemia). The observation that in certain of the malignancies individual values frequently depart from the group trends is emphasized. Sera were found with normal isoagglutinin levels in the face of low total γ-globulin values and vice versa. These findings indicate that some of the factors controlling isohemagglutinin levels may differ from those controlling 6.6S γ-globulin levels.