Abstract: High altitude pulmonary edema (HAPE) is a result of leaking of the fluids from blood vessel to the lung tissue due to pulmonary artery hypertension in the high altitude place, which happens very quickly and shows high mortality. Sildenafil (SIL) can prevent HAPE by expanding pulmonary vessels; however, only oral tablets and injections of SIL are currently available. The formulations have the disadvantages of high doses, inconvenient use, and high systemic side effects. Here, liposomal sildenafil (LS) was prepared for pulmonary delivery and the prevention of HAPE was explored. The ammonium sulfate gradient method was used for the preparation of LS with a high entrapment efficiency of nearly 100%, the particle size of 116.97 nm, and the zeta potential of -30.93 mV. All animal experiments had been approved by the Ethics Committee of Academy of Military Medicine, Academy of Military Sciences, and carried out in accordance with relevant guidelines and regulations. The dose (3 mg·kg^-1 SIL) of sildenafil suspensions, LS or blank liposomes was intragastrically or intratracheally administered to the lungs of mice. The mice with or without treatment were put in the hypobaric oxygen chamber of 5 000 m altitude for 1 h. In the open field text the model mice had the shorter total distances and longer dead time than the healthy mice and they showed the lower percutaneous oxygen saturation (SpO₂), the higher tumor necrosis factor-α (TNF-α) levels of and the lower reduced glutathione (GSH) in the lung tissues. By contrast, oral LS remarkably modified the moving ability of the mice and they had the higher SpO₂ than the model mice and the similar TNF-α and GSH levels to the healthy mice. Sildenafil suspensions and LS with the same dose (3 mg·kg^-1 SIL) were intratracheally administered to mouse lungs, respectively, and the mice of the model group and the treatment groups were put in a hypobaric oxygen chamber for predetermined time. In the rotating rod experiments, the mice in the model group showed shorter drop latency and more drop times than those in the healthy group, indicating that the physical activity of the mice was improved due to treatment. The inflammatory cytokines, TNF-α and interleukin-1β (IL-1β) in the blood of model mice were higher than those from the healthy group and they decreased after treatment, where the LS group maintained the lowest level close to the normal level. IL-1β in the blood of mice in the LS group was lower than that in the SIL group (P < 0.05) 1 hour and 48 hours post-hypoxia. Hypoxia inducible factor-1α (HIF-1α) in the lung tissues of model mice increased but decreased to the normal range after treatment. Moreover, HIF-1α in the LS group was lower than that in the SIL group, where the values were significantly different 48 hours post-hypoxia (P < 0.01). Inhaled liposomal sildenafil is a promising medication for the prevention of HAPE.