A man has died and police have declared a critical incident today following a road crash in western Sydney that has led to the closure of a major highway.

Motorists are being diverted this morning due to the closure of the Great Western Highway in both directions at St Marys, between Glossop and Sydney streets.

Events began at about 4 am when a marked police car stopped near a dark-grey Holden Insignia sedan parked on Mamre Road at St Marys.

The alleged driver of the Holden Insignia has been arrested and is under police guard in hospital. (Nine)

When the driver of the Holden allegedly accelerated away towards the Great Western Highway, police pursued but lost sight of the vehicle.

The Holden then hit a silver Toyota Corolla hatchback. The male driver of the Toyota, who was unconnected to the police activity, died at the scene.

He is yet to be formally identified but is believed to be aged in his forties.

The driver of the Holden allegedly fled the scene on foot.

A 43-year-old man, alleged to be the driver of the Holden, was arrested shortly later on Chapel Street.

He has been taken to Nepean Hospital under police guard for mandatory testing.

The male driver of the Toyota hatchback died at the scene of the crash. (Nine)

A crime scene has been set up and a police critical incident team is investigating the events.

The investigation is also subject to an independent review.

Diversions are in place for motorists,

Light vehicles are being directed to Glossop, Brisbane and Sydney streets in both directions.

Heavy vehicles can use Mamre Road, the M4 and the M7.

Anyone with information should contact Crime Stoppers: 1800 333 000.

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