Metabolic properties of the four subclasses of human IgG were investigated by performing 47 turnover studies in individuals with normal IgG serum concentrations, as well as in patients with an increased level of one of the subclasses. Studies in 12 subjects with normal IgG serum concentration showed that the average biologic half-life of G(1), G(2), and G(4) was 21 days, while that of G(3) was only 7.1 days. Fractional catabolic rates of G(1), G(2), and G(4) were 6.9 to 8% of the intravascular pool per day. G(3), however, had a higher fractional catabolic rate, amounting to 16.8% of the intravascular pool per day. Distribution of the subclasses was such that the intravascular compartment contained 51-54% of the total body pools of G(1), G(2), and G(4), but 64% of the total body pool of G(3).The short survival and high fractional catabolic rate of G(3) is an inherent property of these molecules, and is not due to denaturation during isolation and radiolabeling. This was demonstrated by studies of a patient with a serum G(3)-myeloma protein. The survival of her own protein, separately labeled either in vivo with guanidoarginine-(14)C or in vitro with (125)I, was determined in the patient. Survivals of the in vivo and in vitro labeled proteins were identical.G(1) and G(3) serum concentrations and synthetic rates were determined. The mean serum concentration of G(1) was 6.8 mg/ml and that of G(3) was 0.7 mg/ml, while their synthetic rates were 25.4 and 3.4 mg/kg per day respectively. The low serum concentration of IgG(2) thus results from a combination of high catabolic and low synthetic rates. Studies in 10 patients with multiple myeloma showed that an elevated serum concentration of any IgG subclass was associated with shortened biologic half-life and increased fractional catabolic rate of all subclasses. The implications of this concentration-catabolism relationship are discussed. The serum concentration of nonmyeloma IgG was usually low in myeloma patients and the synthesis of nonmyeloma IgG was somewhat decreased, suggesting that low serum concentrations of nonmyeloma IgG result from decreased synthesis, as well as from an increased fractional catabolic rate.