Police are investigating whether two drivers were street-racing before a fatal four-car crash in Sydney's south-west last night.

Investigators say two cars collided on the Hume Highway at Greenacre just after 6:30pm (AEDT).

The Mitsubishi Lancer and red Nissan Pulsar then crossed the median strip and crashed head-on into two other cars.

An 18-year-old man who was a passenger in the Mitsubishi died at the scene.

The 21-year-old driver of the Lancer, who police say is a cousin of the dead man, was rushed to Liverpool Hospital with serious head injuries.

Four other men, including the 23-year-old driver of the red Nissan, escaped the crash with minor injuries.

The Hume Highway was closed for several hours while crash investigators examined the scene and several of the cars have been seized for further examination.

All of the drivers had mandatory blood tests to check for drugs and alcohol.

Inspector Phil Brooks says it will be some time before the investigation is completed, but speed was a factor.

"With the wet weather on the roads, vehicles travelling at speed involved in crashes will almost certainly lead to a fatal outcome," Inspector Brooks said.

"Just before Christmas, this is a very sad and tragic reminder of just how dangerous the roads can be when speed and wet weather is involved."