The names of the victims were not released.
The crash occurred about 2:05 p.m. in the southbound lane of I-55 at mile post 24 in Pin Oak Township, which is four miles east of Edwardsville.
A 1963 Oldsmobile carrying two people was traveling north on I-55 when it crossed over into the southbound lane.
"For some unknown reason it went through the median and crossed over into the southbound traffic and started to slide sideways," said Illinois State Police Master Sgt. Dennis Bauers.
Bauers said the Oldsmobile was then struck on the driver's side by a 1994 Subaru station wagon carrying three people.
According to the Madison County coroner's office, identifying the victims will be difficult due to the severity of their burns. Each of the victims were pronounced dead at the scene.
Keith Alldredge, of the Marine Fire Department, which is located about seven miles from the accident site, responded to the accident.
"When we got there both vehicles were fully involved in fire," said Alldredge.
Alldredge said that one of the victims was lying outside of a vehicle.
"This was a very serious crash," said Bauers. "I don't recall a five-person fatality in the past couple years."
The accident resulted in major traffic delays in the north and south directions of I-55 for several hours. Motorists traveling south were led on a detour around the crash. The southbound lanes were closed until 7 p.m.
