One in five deaths around the world is caused by sepsis, also known as blood poisoning, shows the most comprehensive analysis of the condition.
The report estimates 11 million people a year are dying from sepsis - more than are killed by cancer.
The researchers at the University of Washington said the "alarming" figures were double previous estimates.
Most cases were in poor and middle income countries, but even wealthier nations are dealing with sepsis.
What is sepsis?
Sepsis is also known as the "hidden killer" because it can be so hard to detect.
It is caused by the immune system going into over-drive. Instead of just fighting an infection, it starts attacking other parts of the body too.
Ultimately it causes organ failure. Even survivors can be left with long-term damage and disability.
Bacteria and viruses that cause diarrhoeal infections or lung diseases are the leading triggers of sepsis.
Why the jump in numbers?
Previous global estimates, which came up with a figure of 19 million cases and 5 million deaths, were based on just a handful of western countries.
This analysis, published in the Lancet and based on medical records from 195 nations, shows there are 49 million cases a year.
The 11 million deaths from sepsis account for one in five of all deaths around the world.
"I've worked in rural Uganda, and sepsis is what we saw every single day," said researcher, assistant professor Kristina Rudd.
"My colleagues treating patients on the ground in low- and middle-income countries every day have been saying this for years, that sepsis is a major problem.
"So in a way I wasn't actually that surprised - on the other hand I didn't expect it to be double the previous estimate."
The good news in this analysis is that cases and deaths have fallen since 1990.
The hope is understanding the true scale of the problem will raise awareness and save more lives.
Who is affected?
The overwhelming majority of cases (85%) are in low- and middle- income countries.
Children were most at risk with four in 10 cases in children under the age of five.
But even in the UK, sepsis is a challenge. The death rate is higher than in countries such as Spain, France and Canada.
There are around 48,000 deaths from sepsis in the UK each year, the report shows.
There has been a big push within the health service to identify the signs of sepsis more quickly and to begin treatment.
What can be done about it?
Reducing the number of infections can reduce the number of cases of sepsis.
For many countries, this means good sanitation, clean water and access to vaccines.
The other challenge is to get better at identifying patients with sepsis in order to treat them before it is too late.
Early treatment with antibiotics or anti-virals to clear an infection can make a massive difference.
Prof Mohsen Naghavi said: "We are alarmed to find sepsis deaths are much higher than previously estimated, especially as the condition is both preventable and treatable.
"We need renewed focus on sepsis prevention among newborns and on tackling antimicrobial resistance, an important driver of the condition."
What are the symptoms of sepsis?
- slurred speech
- extreme shivering or muscle pain
- passing no urine in a day
- severe breathlessness
- high heart rate and high or low body temperature
- skin mottled or discoloured
- a mottled, bluish or pale appearance
- very lethargic or difficult to wake
- abnormally cold to touch
- breathing very fast
- a rash that does not fade when you press it
- a seizure or convulsion