Police said the drivers of both vehicles died at the scene, about 2km north of Singleton at Rixs Creek.

The region's rescue helicopter has airlifted two passengers in one of the vehicles to Newcastle's John Hunter Hospital.

Both are in a serious condition.

Officers from Hunter Valley Local Area Command said they responded to reports of an accident at the Rixs Creek location about 3:20pm.

Police confirmed their initial inquiries indicate one vehicle was travelling south and one was travelling north when they collided head-on.

No further information, including the age and genders of those involved, is available at this time.

The New England Highway is currently closed at Rixs Creek.

The Transport Management Centre said traffic near the accident scene is being allowed to pass in the break-down lane under "stop-slow" conditions.

A detour via Brisbane Road, behind Rixs Creek near the entrance to Yancoal's Ashton Mine, is being considered by traffic authorities and is currently being assessed.

The TMC is asking all other motorists planning to use the New England Highway between Muswellbrook and Singleton to delay their journey if possible.