The 36-year-old man and 31-year-old woman died after one of the cars strayed into oncoming traffic on the outskirts of Edinburgh in the early hours of Sunday morning.
One car was travelling west along the A720 city bypass, approximately half a mile west of the Sheriffhall roundabout, at around 1.15am when it collided head-on with another car travelling in the wrong direction.
Police said it appeared that one car had strayed onto the wrong carriageway.
It was not clear how the vehicle got on to the road but the closest sliproad from the carriageway, which the motorist may have driven down by accident, is some three miles away at the Straiton junction.
Both drivers sustained fatal injuries. There were no other occupants in the vehicles. Police said the next of kin had been informed.
Officers are appealing to anyone who may have seen either vehicle being driven eastbound on the westbound carriageway or witnessed the accident to contact them.
In a previous similar incident, 80-year-old William Watt from Dalkeith in Midlothian was killed when he drove his Vauxhall Astra westbound along the eastbound carriageway of the bypass and crashed head-on with a Honda Civic near the Straiton junction, on Christmas Day 2005.
Fire and ambulance crews attended the crash but Mr Watt died at the scene.
The male driver and female passenger of the Honda, both 59, were taken to Edinburgh Royal Infirmary where they were treated for minor injuries.
A second fatal collision occurred at around 11am on Saturday on the A701 at the Devil's Beef Tub, about a mile north of the English border.
The collision involved a Silver Renault Megane and a Red Fiat Ducato van, with the driver of the Megane suffering fatal injuries. The driver and one passenger within the Fiat Ducato were taken to Dumfries Royal Infirmary for treatment.
The road was closed for nine hours to allow accident investigation to be completed.
Lothian and Borders Police are appealing for witnesses to both crashes.