Emergency services were called to the Newell Highway at Tomingley following reports of a multi-vehicle crash about 9.30pm on Friday.
A ute and a van had collided about 35km south of Dubbo.
Two men who were passengers in the ute, aged 18 and 19, and a husband and wife in the van, both aged 57, died at the scene.
They are yet to be formally identified.
The male driver of the ute was taken to Dubbo Hospital with suspected leg injuries.
The driver of the ute was taken to hospital with suspected leg injuries. (Tim Pascoe/AAP PHOTOS)
When asked if speed played a role in the crash, NSW Police Inspector Rob Bevern said all factors were being investigated.
"We're not too sure at this stage what has caused it," Insp Bevern said on Saturday.
"There's a number of factors that would have caused this crash overnight, but this stage is too early to determine."
All of those involved in the accident were locals from the greater central west region, Insp Bevern said.
"The impact will be greatly shared across the region, not only through the close-knit community but also through the emergency services personnel that attended," he said.
"All we can say is, as the school holidays roll around, please drive to the conditions, drive to the speed limit, and don't die for a deadline."
A report will be prepared for the coroner.
Traffic on the Newell Highway has returned to normal with the reopening of the road between Tomingley and Dubbo.
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