The rising death toll is attributed largely to the nation's growing number of elderly people, who are especially vulnerable to the flu.
Only about 65 percent of older people get vaccinated, and the annual shots do not protect aging immune systems as well as they do younger ones.
The U.S. death toll surged fourfold from 16,263 in 1976-77 to 64,684 in 1998-99, the Centers for Disease Control and Prevention reported. Flu deaths now average about 36,000 a year, up from 20,000 in previous estimates, the CDC said.
Health and Human Services Secretary Tommy Thompson said the news "that influenza may be taking an even larger toll than we have realized" underscores the importance of flu shots, especially for older people.
The study appears in Wednesday's Journal of the American Medical Association.
While drug breakthroughs in the mid-1990s helped tame AIDS and reduce the U.S. death toll from 51,000 in 1995 to about 15,000 in 2001, the main weapon doctors have against flu - a vaccine - has proven disappointingly ineffective in the most vulnerable population, people 65 and older.
The death toll pales in comparison to that of the worldwide flu epidemic of 1918, which killed more than 20 million people, including 500,000 Americans.
But the new numbers frustrate public health experts who had hoped the development of flu vaccine about 40 years ago would have had a greater effect. Annual flu shots have been recommended for people 65 and older since the 1960s and for those 50 and older since 2000.
Vaccination rates are also dismal - about 30 percent - for another target group, people with high-risk conditions such as diabetes and heart disease, said Dr. Keiji Fukuda, a CDC epidemiologist.
Thompson noted that flu shots are free under Medicare and said new federal rules should help increase vaccination rates by allowing hospitalized Medicare patients to get flu shots without a doctor's order.
For the study, researchers developed a new statistical model to create a more accurate estimate of flu deaths using national mortality and virus surveillance data.
The new model shows that a more lethal virus strain has hit in recent years, contributing to the increase in deaths.
But between 1976 and 1999, the number of U.S. adults 85 and older doubled. And the researchers found that this age group was 16 times more likely to die of flu-related causes than people ages 65 to 69.
Flu can progress to pneumonia and other life-threatening lung infections and can weaken elderly people, making them more vulnerable to other serious ailments, such as heart disease.
The study also found that older people are disproportionately affected by another respiratory virus previously thought to be more common in children.
The researchers estimate there are 11,000 deaths annually from respiratory syncytial virus, which can cause severe cold-like symptoms and pneumonia.
Their study confirmed that RSV is the most common cause of viral death in children under 5. But to researchers' surprise, the study found that 78 percent of RSV deaths occur in people 65 and older.
"We've known for some time that influenza and RSV have a profound impact on public health," said CDC director Dr. Julie Gerberding. "However, these data indicate that the magnitude of the problem is larger than we once thought."
Vaccines against RSV are being developed.
By Lindsey Tanner