Nearly 40% of people with lung cancer have tumor growth in other organs at the time of diagnosis. Current treatment strategies for patients with late-stage lung cancer are primarily palliative and only showed modest efficacy. The current study takes advantage of the hydrodynamic gene delivery technique to evaluate the antitumor activity of interleukin (IL)-15/sIL-15Rα on lung tumors growing in the lungs, liver and kidneys. We demonstrate that hydrodynamic tail vein injection of 2 μg of AG209 DP muIL-15sRα+IL-15 plasmid resulted in serum IL-15/sIL-15Rα reaching a peak level of ~10 μg ml(-1) 1 day after the injection and gradually declined to ~5 ng ml(-1) within 3 days. Quantitative PCR analysis revealed that overexpression of IL-15/sIL-15Rα induced the activation of natural killer and T cells, evidenced by increased mRNA levels of marker genes including granzyme B, perforin, Ifn-γ, T-bet and Cd8 in the lungs, liver and kidneys. Importantly, transfer of the Il-15/sIl-15Rα gene alone, or in combination with gemcitabine chemotherapy, significantly inhibited the tumor growth in these three organs and prolonged median survival time of treated mice by 1.7- and 3.3-fold, respectively. The therapeutic benefits are principally blockade and elimination of tumor growth in the liver and kidneys. Taken together, these results suggest that IL-15/sIL-15Rα-based gene therapy could be an effective approach to treat late-stage lung cancer with metastases in other organs.