A woman has been killed as around 20 vehicles were involved in a major pile-up when roads became treacherous due to thick fog.
The A40 was closed in both directions due to the multi-vehicle crash, which stretched for more than half a mile near Witney in Oxfordshire, the ambulance service said.
The female driver was declared dead at the scene, while two people were taken t o the major trauma unit at the nearby John Radcliffe Hospital in Oxford.
One of the patients, a woman, was fighting for her life, South Central Ambulance Service spokesman David Gallagher said.
A witness to the chaos, pregnant mother-of-two Ami Gaston, said driving conditions had become "really dangerous" when fog made it difficult to see the vehicle in front until drivers were "on top of it".
A further 10 to 15 casualties were treated at the scene following several collisions at around 8.25am. Two people with minor injuries were taken to hospital.
Images showed the mangled wreckage of several cars, with debris strewn across the road.
Miss Gaston, from Carterton, was in the car with her partner when she saw the first vehicle crash about half a mile from the Witney exit, blocking the right lane.
"A man on his own had skidded and crashed into the middle barrier. My partner was driving - we had to swerve out of the right lane to avoid hitting him. His door was open and air bags were released," Miss Gaston said.
"I phoned an ambulance but couldn't stop. My partner wouldn't stop because I am 20 weeks pregnant and didn't want to put us in danger."
The disruption came as poor visibility plagued many travellers across the country on Wednesday morning.
London City Airport had dozens of flights cancelled when fog shrouded its airfield.
The Met Office said the heavy fog, precipitated by low temperatures and clear skies, could descend on much of southern England again on Thursday.
Six vehicles were badly damaged in the A40 incident, while a further 10 to 15 were also involved, with the most serious injuries in the middle of the pile-up.
Mr Gallagher said: "There was a collision towards the front of the queue and the more serious one about half-way down."
He added that three ambulances, three rapid response vehicles and two ambulance officers and an air ambulance car attended the scene.
The incident is likely to cause major disruption for many people travelling across the country following the Christmas break, as the road connects London to Wales.
By mid-afternoon, the westbound carriageway was reopened by police.
A police spokesman said: "Thames Valley Police officers remain at the scene of multi-vehicle collisions on the A40, Witney. Sadly, a woman was pronounced dead at the scene earlier today."
He added: "The eastbound carriageway will remain closed while officers carry out investigations at the site of the collisions. All vehicles which were not involved in the collisions have now been released from the site."
Another witness arrived at the scene later and described the "carnage" as multiple cars swerved and crashed on the busy road.
The woman, who asked not to be named, said she "luckily" saw hazard warning lights ahead as she approached on the slip road from Carterton, and moved on to a grass verge before witnessing the pile-up.
"I saw cars going zooming past me and trying to swerve out the way of the stationary cars but crashing into them," she said.
"I saw one car try to swerve in between a Mini and another car, ending up crashing into the Mini and (flying) up in the air.
"I saw two cars swerve as they braked so hard and go flying into the barrier in the middle of the road ... it was carnage."