Background: Respiratory syncytial virus (RSV) is becoming increasingly recognized as a serious threat to vulnerable population subgroups. The Epidemiology, Burden, and Cost (EBC) of RSV Infection Study is a retrospective cohort study of adults hospitalized for acute respiratory infection (ARI) designed to estimate the population burden of RSV especially for specific groups such as the elderly, pregnant women and solid organ transplant patients. This paper describes the design and statistical analysis plan for the study. Methods: The study population will consist of residents of Allegheny County, Pennsylvania ≥18 years of age who were hospitalized in Pennsylvania during the period September 1, 2015 to August 31, 2018. Several data sources will be used including U.S. Census, Pennsylvania Health Care Cost Containment Council (PHC4), and the electronic medical record for the health system to which the hospitals belong. The algorithm involves: 1) ARI-associated hospitalizations in PHC4 data; 2) adjustment for ARI hospitalizations among county residents but admitted to hospitals outside the county, and 3) RSV detections from respiratory viral panels (RVPs). Key sensitivity analyses will adjust for undertesting for viruses in the fall and spring quarters. The results will be population-based estimates, stratified by age and risk groups. Conclusion: Adjusting hospitalization data using a multiplier method is a relatively simple means to estimate the impact of RSV in a given area. This algorithm can be applied to other health systems and localities to estimate burden of RSV in adults, as well as burden of other respiratory pathogens.