Introduction: Chronic rhinosinusitis (CRS), which affects 9.8% of the Australian population, is largely attributed to the colonisation of pathogenic bacteria, most commonly Staphylococcus aureus. The increasing prevalence of antibiotic resistance in S. aureus impedes effective treatment, leading to prolonged morbidity in patients. Bacteriophage therapy has recently emerged as a potential solution and is being trialled worldwide. However, researchers have increasingly found that some S.aureus are also bacteriophage resistant. Patients colonised by such bacteria are not offered phage treatment and have no other therapeutic options. Previous findings from our research have shown that phage generated in the presence of low concentrations of specific antibiotics and phage-resistant S.aureus (newly termed modified phage) can target and kill that phage-resistant strain of S.aureus specifically. Aim: To successfully generate and test the safety and efficacy of modified phage in killing phage-resistant S. aureus sinus infection in vivo. Methods: The tests were conducted in a rat model of sinusitis infected with the phage-resistant S. aureus. Phage titres, Bacterial counts, histology, and biofilm analysis were performed to access outcomes. Results: Low phage titres and normal histology of sinuses and organs after application of high-dose modified phage for 21 days demonstrated safety. Efficacy trials involved (n=72) rats infected with phage-resistant S.aureus randomised to receive 2 concentrations of phage or saline intranasally for up to 7 days. A 1000x reduction in bacterial counts and significant differences (p<0.05) in biofilm biomass and nasal cavity inflammation was seen in phage-treated groups. Conclusion: Modified phage therapy has the potential to transform the lives of CRS patients infected with phage and antibiotic-resistant S.aureus. This therapy can be extended to other infections caused by S.aureus including lung and skin and potentially other bacteria.