Multiple curative phage therapies are being developed to counter multidrug resistant diseases. The leading candidates are now being evaluated in human phase 1 and/or phase 2 clinical trials. Several single patient phage therapies have already concluded, while many others will advance in the future. Phages have been increasingly recognized for their influence on the human immune system including bacterial disease, and may also influence the outcomes of phage therapies. We have analyzed the immunogenicity of Pseudomonas aeruginosa phages in vitro, in animal, and in patient. We quantified the upregulation of 410 genes and downregulation of 206 genes in macrophages exposed to myovirus PAK_P1. This correlated with increased production of several proinflammatory cytokines, including IFNβ, TNF, CXCL1/KC and IL-17A. Peak expression was observed after six hours of phage exposure. Applying gene ontology, we found that macrophage response was largely driven by transcription factor NF-κB, promoting expression of predominantly antiviral responses. We determined that extracted phage DNA induced a similar cellular response to that observed with whole phage particles. In contrast, bacterial LPS toxin induced a differential cytokine. This suggests that TLR9 is largely involved in sensing phage DNA. We observed that TLR2 may also be involved in phage capsid sensing by macrophages. Next, we found that phages in the lungs of mice caused exposed mice to lose significant weight. Weight loss was comparable to airway exposure to LPS toxin. Phage PAK_P1 has also been used to treat infectious disease in humans. Post-treatment analysis of patient serum suggests that 14 days of twice daily treatments promoted generation of phage specific neutralizing antibodies. Applying an antiviral-based framework to our findings indicated parameters that may inform the development of more effective, safer phage therapies in clinical practice.