Police say a lorry travelling southbound in South Gloucestershire went through the central reservation and collided with at least two other vehicles on the northbound carriageway.
Four people have been confirmed as dead, while the lorry driver required treatment.
The motorway was closed overnight between J16 and J14 while emergency services carried out work at the scene.
The Southbound carriageway is now open.
Emergency service personnel have been working tirelessly at the scene in harrowing conditions and I’d like to praise them for the work they’ve done and are still doing. I’d also like to thank the members of the public who courageously went to the aid of those involved in this collision and in some cases rescued them from their vehicles.
Officers from our Collision Investigation Unit are carrying out a full investigation into the causes of the crash and have spoken to the lorry driver involved.