We estimated the possible effects of the next influenza pandemic in the United States and analyzed the economic impact of vaccine-based interventions. Using death rates, hospitalization data, and outpatient visits, we estimated 89,000 to 207,000 deaths; 314,000 to 734,000 hospitalizations; 18 to 42 million outpatient visits; and 20 to 47 million additional illnesses. Patients at high risk (15% of the population) would account for approximately 84% of all deaths. The estimated economic impact would be US$71.3 to $166.5 billion, excluding disruptions to commerce and society. At $21 per vaccinee, we project a net savings to society if persons in all age groups are vaccinated. At $62 per vaccinee and at gross attack rates of 25%, we project net losses if persons not at high risk for complications are vaccinated. Vaccinating 60% of the population would generate the highest economic returns but may not be possible within the time required for vaccine effectiveness, especially if two doses of vaccine are required.