The open-world action title is Activision's first number one of the year, but fails to outperform its predecessor, which achieved greater first week sales in 2009.
The closest challengers to the all-format top spot are once again FIFA Street and FIFA 12 in second and third.
At the tail-end of the chart, Saints Row: The Third re-enters at ten, below Mario & Sonic At The London 2012 Olympic Games and Battlefield 3.
The top ten in full:
1. (-) Prototype 2 (Activision)
2. (2) FIFA Street (Electronic Arts)
3. (3) FIFA 12 (Electronic Arts)
4. (5) Mass Effect 3 (Electronic Arts)
5. (4) Kinect Star Wars (LucasArts)
6. (1) The Witcher 2: Enhanced Edition (Namco Bandai)
7. (6) Tiger Woods PGA Tour 13 (Electronic Arts)
8. (7) Battlefield 3 (Electronic Arts)
9. (9) Mario & Sonic At The London 2012 Olympic Games (Sega)
10. (12) Saints Row: The Third (THQ)
Leisure software charts compiled by Chart Track, (C) 2012 UKIE Ltd.
Watch the live action Prototype 2 trailer below: