Viral respiratory infection (VRI) is the most commonly occurring illness in man, imposing considerable burden on patients and on society. However, to date, no formal study of the economic impact of VRI has been performed. OBJECTIVES: To rigorously quantify the economic impact of viral respiratory disease (VRI) in the US in terms of health-care resource utilization (direct costs) and productivity losses (indirect costs). METHODS: Publicly available databases including the US Census, National Health Interview Survey (NHIS), the Medical Expenditure Panel Survey (MEPS) and the National Ambulatory Medical Care Survey (NAMCS) were used. From these databases, projections regarding population characteristics, physician and emergency-room encounters, prescription and over-the-counter drug utilization, and productivity losses related to VRI were made Data obtained from primary epidemiological research and prospective randomized clinical trials were used to estimate the incidence of VRI in the general population and the rate of secondary clinical complications associated with VRI. RESULTS: Nearly 500 million episodes of VRI occur annually in the US alone. Direct costs associated with VRI are estimated to be $16.8 billion annually and are broken down as follows: physician visits, $6 billion; complications, $3.8 billion; prescription and over-the-counter medications, $4.8 billion. Indirect costs for employed individuals approximate $7.6 billion per year. Physician encounters via a telephone and the internet, productivity losses incurred by caregivers (i.e., parent) of VRI-infected individuals, and costs associated with diminished productivity while at work or home were not included, suggesting that this projection of total VRI costs—$25 billion annually in the US alone—is very likely an under-estimate. CONCLUSIONS: Viral respiratory infections impose a significant clinical and economic burden to society, approaching or surpassing the aggregate costs of many common chronic diseases. The resultant clinical and cost ramifications attributable to this common acute condition warrants increased attention from health-care providers and policy makers.