Two men and two women have died in a collision involving a tanker, car and van on the A44 near Aberystwyth, say Dyfed-Powys Police.
It is believed that the four are from the same family.
An infant girl is also in a serious condition at the University Hospital of Wales in Cardiff after the crash which happened between Llangurig and Ponterwyd just before 15:00 BST.
Police say the road will remain closed for some time. Diversions are in place.
The collision happened around 15 miles (24km) from Aberystwyth, near Eisteddfa Gurig, between the villages of Llangurig in Powys and Ponterwyd in Ceredigion.
The A44 is closed between the A4159 (Lovesgrove Roundabout, Aberystwyth) and the A570 (Llangurig).
The child, who has head injuries, was airlifted to hospital in Cardiff.
In all, two air ambulances and five other ambulances were sent to the scene along with other emergency crews.
A Welsh Air Ambulance service statement said its Welshpool-based medics treated a female child at the scene before she was flown to Cardiff's University Hospital of Wales.
Mid and West Wales Fire and Rescue Service said they were called at about 15:00 BST and sent two pumps to the scene. There are still two appliances at the scene making the area safe.
Eluned Thomas, from Eisteddfa Gurig farm, about two miles away, said she rang for the emergency services after a woman alerted her to a "very, very bad accident" just down the road.
"The woman said a fuel tanker was coming up from Llangurig and a car went straight into it," she said.
Ms Thomas told Radio Wales the A44 was a very winding road, adding: "Accidents happen all the time on this road and it's the main road from the Midlands to Aberystwyth."
She said the woman had asked her to call emergency services because there was no mobile phone coverage in the area.
Initial reports said the collision had involved a tanker and a car, but police later confirmed a van was also involved.
The A44 is one of the main roads in mid Wales and links Ceredigion with Powys. The road is closed for 21 miles (34km).
The stretch between Llangurig and Aberystwyth is around 25 miles (40km) long.