Pseudomonas aeruginosa is an important cause of life-threatening nosocomial pneumonia and prone to multidrug resistance. Especially at risk are patients with weakened immune systems and chronic respiratory disorders. Considering the scarcity of new antibiotics, the use of bacteriophage (phages) as an alternative therapy has re-emerged. While several recent animal studies have demonstrated the therapeutic potential of phages for treating pseudomonal lung infection in healthy immunocompetent animals, it remains unknown whether phages are effective in the setting of immunodeficiency or have untoward immunostimulatory effects during inflammation (e.g. cystic fibrosis). We show that inhaled phage therapy can cure acute pseudomonal lung infection in severely immunodeficient hosts lacking innate and adaptive lymphocytes (Rag2-/-Il2rg-/- mice). Moreover, phage prophylaxis also prevented lethality in this setting. Although phage therapy efficacy was lymphocyte-independent, we demonstrate that innate effectors, in particular neutrophils, were critical for therapeutic effect. Concerning immunogenicity, high dose respiratory administration of phages did not promote obvious cytokine production. We further investigation into the effect of phage on neutrophil reactive oxygen species (ROS) production and neutrophil extracellular trap (NETs) formation. Using human neutrophils, we confirm that highly purified phage alone do not promote ROS, nor exacerbate phorbol myristate acetate and calcium ionophore induced ROS. In addition, phages do not dampen the formation of NETs. This study suggests that phage therapy may provide a safe and efficient therapy for P. aeruginosa in the context of immunodeficiency.