The trunk road between Aultguish, east of Loch Droma, and Ullapool, was not re-opened until around 3pm after gritters, tractors and a snow blower battled to clear 2m high drifts.
The A832 to the south and west was also closed, along with the Bealach na Ba hill route to Applecross.
In Aberdeenshire and Moray, roads shut by snow included the A93 between Glenshee and Braemar, and the A939 between Cockbridge and Tomintoul.
An amber severe weather warning for up to 50cm of snow across inland northern Scotland away from the west coast is due to remain in force until noon on Saturday.
It will be followed by a lesser yellow warning for up to another 15cm of snow and ice from 3pm on Saturday and for the whole of Sunday.
The Scottish Fire and Rescue Service said it was called out to the Loch Droma snowdrifts around 5.15am and units remained at the scene.
The cars and their 40 occupants were cleared from 7-10am using snowploughs and diggers, with no injuries reported.
Police Scotland said: “A major incident was declared overnight in response to 22 vehicles trapped in snowdrifts near Loch Droma.
"Emergency services attended and carried out welfare checks, evacuating two people.
"Welfare centres were set up at Ullapool and Aultguish.”
The rescue also involved Highland Council, NHS Highland, the Scottish Ambulance Service, Scottish Fire and Rescue Service, road maintenance firm BEAR Scotland and mountain rescue teams.
Superintendent Maggie Pettigrew, of Police Scotland’s Highland & Islands division, said: “Due to severe weather conditions on the A835 between Braemore and Loch Droma, officers worked as part of a multi-agency response to assist a number of drivers and passengers who were stranded within their vehicles.
"These vehicles have now been cleared away from the scene and all individuals safe and well.
"Other drivers are asked to avoid the area or consider avoiding travel if driving conditions are difficult in your area.
"Officers are currently still at the scene.”
A Highland Council spokesperson said : “We have diverted our roads operatives to assist our partners in this incident.
"This will have a knock on effect on our ability to provide winter maintenance elsewhere in this area.
"The surrounding roads in this area remain closed or extremely difficult to access and we would urge people not to attempt to travel at this time.”
NHS Highland chief executive Pamela Dudek said : “We are assisting in the response with support at welfare centres and are standing up the resilience Care for People group for the west coast to ensure everyone in the area is kept safe and well during this adverse weather.”
The Highland Main Line was reopened between Dalwhinnie and Inverness after Network Rail snowploughs cleared drifts which had shut the route since Thursday.
However, CalMac suspended sailings on its main Arran route because of bad weather, and between Mallaig and Armadale in Skye, and the Small Isles.