The findings in the New England Journal of Medicine are from the first randomized, controlled trial to compare high and standard doses of flu vaccine in older people.
"Until this trial came out we didn't know if it was going to be clinically better or not, and now we know it is better," said lead author Keipp Talbot, assistant professor of medicine at Vanderbilt University.
The study was funded by Sanofi Pasteur and compared the company's Fluzone High-Dose inactivated influenza vaccine to the standard-dose Fluzone vaccine.
The high-dose contains four times the amount of antigen as the standard dose.
The high-dose flu vaccine was 24 percent more effective than the standard-dose vaccine in protecting those over 65 against influenza and its complications, which can include pneumonia and heart failure.
It was also found to be safe and induced "significantly higher antibody responses" than the standard dose did.
Side effects included greater arm soreness following the injection.
The study involved nearly 32,000 people at 126 research centers in the United States and Canada.
The flu causes tens of thousands of deaths each year and more than 200,000 hospitalizations, according to background information in the article.
"These new data are important because they show that the improved antibody response that is evident in blood samples does in fact translate into a better clinical outcome -- prevention of influenza virus infection in recipients of the high-dose vaccine," said Nicole Bouvier, assistant professor of medicine, infectious diseases and microbiology at the Icahn School of Medicine at Mount Sinai in New York. She was not involved in the research.
Ambreen Khalil, an infectious disease specialist at Staten Island University Hospital in New York, also described the study as "very well done."
"However it is important to bear in mind that these results are based on results from 2011 to 2013, while influenza activity is variable every year," she said.