In the present study, a novel dry small interfering RNA (siRNA) powder for inhalation, containing polyethyleneimine (PEI) as a delivery vector, was produced by spray freeze drying (SFD). The powder had spherical and highly porous structure of approximately 10 μm in diameter with high aerosol performance for emission and lung delivery. The reconstituted siRNA/PEI complex after dissolution of the powder had almost the same physicochemical properties and in vitro gene silencing activity as the original one constituted in the sample solution before SFD, showing that the integrity of the siRNA was maintained. In in vivo studies of intratracheal administration into lung metastasis mice and healthy mice, powder with a low dose of 3 μg siRNA exhibited strong and specific gene silencing activity against tumors metastasized to the lungs, whereas it caused no significant histological changes, lactate dehydrogenase leakage, or inflammatory cytokine induction in the lungs. These results strongly indicated that inhalable dry siRNA/PEI powders can provide effective pulmonary gene silencing without severe lung injury and that SFD can be applied to the production of such powders.