Insulin-(131)I was administered intravenously to normal subjects, to patients with maturity-onset diabetes and normal renal function, and to nondiabetic patients with renal failure. The ensuing plasma disappearance curves of immunoprecipitable radioactive insulin were determined, and these data were analyzed in a variety of ways. Firstly, fractional irreversible loss rates of insulin from plasma were calculated and found to be greatly diminished in patients with renal failure (t((1/2)) = 39 min), as compared with normal (t((1/2)) = 15 min) and diabetic subjects (t((1/2)) = 12 min). Secondly, plasma insulin-(131)I disappearance curves were resolved into sums of three exponentials by the method of "peeling," and values for the resultant three slopes and half-lives were determined. Patients with normal renal function had similar values for all parameters, while those patients with renal failure were differentiated on the basis of the slope of the last component, with a prolongation of its half-life to 275 min (approximately twice normal). Finally, a three pool model was formulated to describe the kinetics of plasma insulin disappearance in man, representing plasma (pool 1), interstitial fluid (pool 2), and all tissues in which insulin is utilized and degraded (pool 3). The proposed model adequately describing the disappearance curves of insulin-(131)I observed in all patients indicated that volumes (per cent body weight) of pool 1 (4.04) and pool 2 (10.11), calculated on the basis of the model and the experimental data, corresponded closely to estimates of plasma and interstitial fluid volumes obtained by independent means. It also demonstrated that patients with renal failure were characterized by a decreased removal rate of insulin from pool 3 and an increased recycling rate of insulin from pool 3 to pool 2. It is concluded that the proposed model represents a reasonable description of the kinetics of insulin distribution and degradation, and that its use provides quantitative insights into the physiology of insulin metabolism.