Three men, all aged in their 20s, were killed in the collision, which occurred between a lorry and a car in the Omagh Road area at Garvaghy in County Tyrone.
A fourth young man, also aged in his 20s, is in hospital with serious injuries.
The road reopened this evening more than 12 hours following the collision, which happened at around 1.50am on Monday.
Sinn Féin MP Órfhlaith Begley said the death of the men and serious injury of another on the A5 road at Garvaghey early this morning has stunned the entire community.
The West Tyrone MP said: “I wish to extend my deepest sympathy to the families of the three young men killed and of the young man seriously injured in this accident at Garvaghey.
“The scale of this tragedy has stunned the entire community but everyone will rally around in support all those affected in what will be difficult days ahead.
“I wish to pay tribute to the emergency services for all their efforts at the scene.
SDLP West Tyrone MLA Daniel McCrossan meanwhile has expressed his shock at the tragedy.
Mr. McCrossan said: “This heartbreaking news is deeply shocking and distressing to us all. My thoughts are with the families and friends of these young victims whose lives have been cut short in such tragic circumstances.
“My thoughts are also with the fourth victim who has been taken to hospital for treatment and I would like to wish him a speedy and full recovery.
“I would also appeal to anyone with information about the incident to contact the police.”
Appealing for anyt witnesses to come forward, PSNI Inspector Hicks said: “At around 1.50am, it was reported that a car and a lorry were involved in the incident.
“Three males, all aged in their 20s sadly died at the scene. A fourth male, also in his 20s, was taken to hospital for treatment to serious injuries.
“Enquires are continuing and anyone who was in the area at the time and may have witnessed the incident or who has dashcam footage or any other information, should contact police on 101 quoting reference number 240 27/12/21.”
The Omagh Road was closed in both directions between the Curr Road and the Greenmount Road, through until late on Monday afternoon.