The production of recombinant human interleukin-2 (RIL-2) in large amounts has made possible studies of the in vivo effects of this lymphokine in the normal murine host. We have studied a variety of routes of administration of RIL-2 in mice to maximize the bioavailability of this lymphokine. The serum half-life after intravenous administration was 1.6 +/- 0.3 min (mean +/- SEM, n = 3). Intraperitoneal and subcutaneous administration resulted in RIL-2 serum levels greater than or equal to 10 units/ml for 3-5 h, and was prolonged by gelatin for 7-11 h. Continuous infusion of RIL-2 was accomplished with osmotic pumps placed intraperitoneally or subcutaneously, and resulted in RIL-2 serum levels greater than or equal to 8 units/ml for greater than 4 days. RIL-2 given intraperitoneally three times daily for 3 days enhanced natural killer activity of splenocytes as measured by lysis of YAC cells. Specific augmentation of C57BL/6 splenocyte cytotoxicity to a secondary challenge of irradiated allogeneic P815 was found in mice receiving RIL-2 intraperitoneally three times daily for 3 days. The continuous administration of RIL-2 over a 4-day period resulted in the in vivo generation of lymphokine-activated killer cells in the spleen and peritoneal exudate. The exogenous administration of RIL-2 in the normal murine host enhances three different cell-mediated cytotoxic mechanisms and has potential applications in the treatment of tumors and immunodeficient conditions.