Interleukin 2 (IL 2) activity was measured in the serum of mice, using a bioassay, following various methods of IL 2 administration. IL 2 has a serum half-life of 3.7 min +/- 0.8 min (mean +/- SD) in mice after i.v. injection, and a serum IL 2 titer of 2 units/ml could be sustained for less than 30 min after injection of highly concentrated IL 2 solutions. Intraperitoneal (i.p.) and subcutaneous (s.c.) injection of similar amounts of IL 2 prolonged the duration of serum IL 2 activity at greater than 2 units/ml for 2 and 6 hr, respectively. Administration of IL 2 in a gelatin base was capable of sustaining serum IL 2 levels at greater than 2 units/ml for up to 16 hr. The reason for the short in vivo half-life of i.v. injected IL 2 was studied. No inhibitors of IL 2 could be detected in our cell growth assay of IL 2 activity. Exposure of IL 2 to mouse blood or serum had no impact on IL 2 titers. To evaluate the possibility that IL 2 was binding to lymphoid cells in vivo, the fate of IL 2 was studied in nude mice, in mice 4 days after 1000 rads total body irradiation, and in splenectomized mice. The serum half-life in these modified mice was identical to that in normal mice. The kidney appeared to be the main site of IL 2 clearance. The rates of IL 2 disappearance in mice rose from a control T 1/2 of 2.5 to 3.5 min in sham-operated animals to up to 84 min in mice with ligated renal pedicles. IL 2 was not excreted in an active form in the urine and ureteral ligation had only a small effect on the serum half-life of IL 2, implying probable renal tubular catabolism of filtered IL 2.