The collision, which involved a Fiat Stilo and a MAN HGV, happened on the eastbound carriageway of the M8, around one mile east of Harthill about 1am.
There are reports the Fiat Stilo was travelling west on the eastbound carriageway, having joined it at junction 3A, before it collided with the HGV which was heading east.
A 19-year-old man from Bathgate who was driving the car died at the scene, while the 39-year-old lorry driver was not injured.
The eastbound carriageway of the M8 was closed between junction five, Shotts, and junction four, Whitburn, for around five hours while investigations were carried out at the scene. One lane reopened around 6am, with the full carriageway reopened about 8.50am.
Inspector Richard Latto said: “At the moment we are working to establish the circumstances leading up to this collision, and would appeal for anyone who may have been in the area at the time, and who may have seen what happened, to contact police on 0131 311 3131.”
Anyone with any information should contact Lothian and Borders Police on 0131 311 3131, or the charity Crimestoppers in confidence and complete anonymity on 0800 555 111.