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We have previously shown that aerosol interleukin-2 (IL-2) increased the number of intravenously injected human natural killer (NK) cells in the lungs. In this study we investigated whether this increase was secondary to NK cell proliferation and determined the site of the proliferation.Nude mice with osteosarcoma lung metastases were injected with NK cells and treated with aerosol IL-2 or aerosol PBS. BrdU was injected prior to euthanasia to identify proliferating NK cells. The percentage of proliferating NK cells in the lung, bone marrow, spleen, and liver was determined using flow cytometry. Survival studies for mice with osteosarcoma lung metastasis treated with aerosol PBS, aerosol IL-2 alone, aerosol PBS plus NK cells, and aerosol IL-2 plus NK cells were also performed.Treatment with aerosol IL-2 induced the proliferation of injected NK cells in the lung. Aerosol IL-2 did not increase the proliferation of NK cells in the spleen and liver. Treatment with aerosol IL-2 and aerosol IL-2 plus NK cells increased the overall survival of mice with osteosarcoma lung metastasis.Aerosol IL-2 increases lung NK cell numbers by stimulating local NK cell proliferation. Aerosol IL-2's effect on NK cell proliferation is organ specific, which makes it ideal for the specific targeting of lung metastasis. Aerosol IL-2 plus NK cell therapy induced metastatic regression and increased overall survival demonstrating the potential of this therapeutic approach for patients with osteosarcoma. Pediatr Blood Cancer 2014; 61:1362–1368. © 2014 Wiley Periodicals, Inc.