The drivers were among the six taken to hospital, where they will undergo mandatory testing.

One of the cars also crashed into a bronze Mazda in a secondary collision, but none of the Mazda's occupants, including a toddler, were injured.

Inspector Brennan said police would not release the ages and genders of the people killed until their families had been notified.

The highway was closed in both directions for several hours after the crash, reopening shortly before 3pm on Friday.

Earlier, specialist crash investigators deployed a drone at the scene to take aerial photos of the wreckage as part of their investigation.

Inspector Brennan said though it was not yet clear what had caused the crash, it should be a reminder to all drivers.

"I can't tell you whether speed was a factor in this particular instance, but it's always good to remember that these things can happen so quickly," she said.

"Even if the signposted speed limit says 100 kilometres an hour, it may not be safe to drive at that speed.

"People need to drive to the conditions and be vigilant of what's around them."

Inspector Brennan urged anyone with information on the crash to contact Yass Police Station on 6226 9399, or Crime Stoppers on 1800 333 000, or via the website.