Emergency services were called to the scene of the crash on the Great Western Highway, about 15km north of Lithgow in NSW.
The crash involved five vehicles and occurred just before 1pm.
Police confirmed that two people had died and 15 others were treated by paramedics before being transported to hospital for injuries ranging from minor to critical.
Emergency services, including — NSW RFS (@NSWRFS) #RFS crews are in attendance at a significant incident on the Great Western Hwy. The road is closed in both directions between Barton Ave, Wallerawang and Range Rd in Meadow Flat and will be for some time. More information at https://t.co/0cqoFesW5W pic.twitter.com/e4hUu37E5eDecember 29, 2023
Detective Superintendent Paul Glinn said it was a "significant scene" attended by 80 rescue personnel including police, paramedics, Fire and Rescue NSW, Rural Fire Service, VRA Rescue and the State Emergency Service.
Specialist police had also been called to assist with an investigation into the crash.
"The investigation is in its infancy, there are investigators on scene from the local police district and we also have crash investigation police here to undertake a review of the circumstances of the collision," he told reporters.
"We would be appealing for members of the public perhaps that were in the area that may have witnessed the collision or have some sort of dash cam footage to make contact with us."
The Great Western Highway is closed in both directions and is expected to remain a crime scene for a considerable amount of time.
Drivers are urged to avoid the area.
Det Supt Glinn reminded drivers that roads were busy due to people travelling for the holidays and urged people to slow down.
"There's lots of police and others out and about on the roads and we're doing our best to make sure that people make good decisions," he said.
"But we also encourage (drivers) to make sound decisions each time you get into a motor vehicle to complete your journey safely."
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