The fatal accident involving three cars happened on Belgrave Middleway, near Edgbaston, at around 1am this morning.
Horrifying pictures of the scene show debris from the mangled wreckage of cars scattered on the road.
The Force Support Unit of West Midlands Police said on their Twitter account that the road will be closed from Islington Row to Bristol Street "throughout Sunday".
Police officers dealing with the horrific incident described it as "very difficult and upsetting".
One person ordering food at a nearby McDonalds – who described it as "the most horrible thing I have ever witnessed" – said the crash caused such a noise people rushed out of their cars and flats.
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Lizzy Bowers said on Facebook: "I was at the McDonald's drive through when this happened, everyone ran out their cars and flats to come look over the edge and it was the most horrible thing I have ever witnessed.
"I hope everyone involved is okay, especially this close to Christmas. Tragic."
Shortly after the incident, police tweeted: "All first responders at the scene are doing their very best in very difficult and upsetting circumstances. This is a very serious incident."
The Hazardous Area Response Team of West Midlands Ambulance Service described it as a "significant incident".
People took to social media to express their horror at the news of fatalities.
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One person said on Twitter: "Thinking of those and their families caught up in the horrific crash in Birmingham."
Another added: "Brutal to hear six dead from a car crash in Birmingham last night.
"Thoughts are with their families, this close to Christmas you wish that on no person."
Sgt Alan Hands – from the Collision Investigation Unit – said: "We are currently dealing with a very serious collision and working with partner agencies to establish what caused this collision to happen.
"Our thoughts and deepest sympathies remain with the families of those who have very sadly lost their lives this morning and those who have been injured or caught up in this incident."
All first responders at the scene are doing their very best in very difficult and upsetting circumstances. This is a very serious incident. If you saw the crash happen or the circumstances leading up to it, please call us now on 101.
— West Midlands Police (@WMPolice) December 17, 2017
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