As a devastated Mr Cole stood surveying the carnage around him on Picton Road in Wilton on Friday morning, he did so with the knowledge that one of his drivers - one of his friends - would never see his young family again.

Mr Cole, who owns Campbelltown City Car Carriers, said his employee, named only as Mick, was one of two truck drivers who died in a horrific head-on crash on Picton Road about 5am on Friday.

Police said it was dark and the road was wet when the two trucks - a car-carrier and a semi-trailer - collided head-on on a bridge several kilometres east of Picton Road's intersection with the Hume Motorway.

The car-carrier burst into flames, which engulfed the cabin, trapping 39-year-old Mick inside.

Police initially said driver of the car-carrier had "not been found".

Firefighters extinguished the fierce blaze, allowing police to examine the burnt-out cabin, Inspector Michael Bright, from NSW Police, said.

More than two hours after the crash, police confirmed the body of Mick had been found inside his truck.

"It was quite an intense fire, and it took us a while for the fire to be extinguished, and then it took a while to determine that the male was in the vehicle," he said.

The driver of the semi-trailer, a 32-year-old man, was thrown from his rig and died at the scene. Remarkably, a kelpie dog that was inside the semi-trailer survived and was being cared for by a veterinarian.

At the crash scene on Friday morning, Mr Cole said the death of Mick, who was married with a young son, had "destroyed all of us".

"He wasn't just an employee, he was a friend," Mr Cole said.

"You could not wish to have a nicer employee, but more so, a friend. Always obliging, always having a laugh and a joke, and he's going to be sadly missed.

"Just to Mick's family: My heart goes out to you all, and God bless you, I love you."

Inspector Bright said a close friend of one of the drivers was driving another truck a short distance behind his friend on Picton Road, and was among the first people to come across the crash.

Nothing could be done to save the drivers, Inspector Bright said.

"Initial responders were faced with a horrific scene," he said.

"It's a significant crash, we've got a truck on fire with someone trapped, and another male who is deceased.

"The fire was intense ... There was nothing unfortunately that could be done for the male inside [the burning truck]."

Inspector Bright said both drivers were at the beginning of their shifts, and it was dark and wet when the crash occurred.

"It was 5am, so it was still night time. I believe it was raining, and you're coming down a hill into the bridge area, so it would have been slippery as well," he said.

Police from the Metropolitan Crash Investigation Unit are at the scene.

The Transport Management Centre said Picton Road had been closed between MacArthur Drive and Wilton Road in Wilton, and is expected to remain so for several hours.

Motorists have been told to avoid Picton Road, and use Appin Road as an alternative route.

Inspector Bright said Picton Road was "notorious for having major accidents".

The most recent fatality occurred last month, when a man died and several other were injured not far from the scene of Friday's crash.

One of the worst crashes on the same stretch of road in recent years was in 2009, when five members of a family who had fled Afghanistan in search of a new life were killed in a crash.

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