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Background During the ongoing COVID-19 pandemic, healthcare-associated transmission of respiratory viral infections (RVI) is a concern. To reduce the impact of SARS-CoV-2 and other respiratory viruses on patients and healthcare workers (HCWs) we devised and evaluated a multi-tiered infection control strategy with the goal of preventing nosocomial transmission of SARS-CoV2 and other RVIs across a large healthcare campus. Methodology From January-June 2020, a multi-tiered infection control strategy was implemented across a healthcare campus in Singapore, comprising the largest acute tertiary hospital as well as four other subspecialty centres, with more than 10,000 HCWs. Drawing on our institution’s experience with an outbreak of Severe Acute Respiratory Syndrome (SARS) in 2003, this strategy included improved patient segregation and distancing, and heightened infection prevention and control (IPC) measures including universal masking. All symptomatic patients were tested for COVID-19 and common RVIs. Results A total of 16,162 admissions campus-wide were screened; 7.% (1155/16162) tested positive for COVID-19. Less than 5% of COVID-19 cases (39/1155) were initially detected outside of isolation wards in multi-bedded cohorted wards. Improved distancing and enhanced IPC measures successfully mitigated onward spread even amongst COVID-19 cases detected outside of isolation. COVID-19 rates amongst HCWs were kept low (0.13%, 17/13066) and reflected community acquisition rather than nosocomial spread. Rates of healthcare-associated-RVI amongst inpatients fell to zero and this decrease was sustained even after the lifting of visitor restrictions. Conclusion This multi-tiered infection control strategies can be implemented at-scale to successfully mitigate healthcare-associated transmission of respiratory viral pathogens.