Twelvetrees comes in for Manusamoa Tuilagi, while Joe Marler replaces Alex Corbisiero in two changes from the side that started against New Zealand In December.
Dylan Hartley, Toby Flood and David Strettle come on to the replacements' bench for David Paice, Freddie Burns and Jonathan Joseph respectively.
England Head Coach Stuart Lancaster said:
"We are happy to stick with the team that did so well against New Zealand, especially in light of the fact that they have all been in good form for their clubs since then.
"There were some very tight calls, with some experienced players coming back into contention, and I am sure the bench will have a significant impact on the game.
"We can't wait to get back to Twickenham and hopefully experience the same atmosphere as the autumn when the crowd was superb. It means a lot to the players to have such support in the ground and watching on television."
England (v Scotland, Saturday, 4pm, Twickenham Stadium)
15. Alex Goode (Saracens, 6 caps)
14. Chris Ashton (Saracens, 29 caps)
13. Brad Barritt (Saracens, 11 caps)
12. Billy Twelvetrees (Gloucester Rugby, uncapped)
11. Mike Brown (Harlequins, 11 caps)
10. Owen Farrell (Saracens, 12 caps)
9. Ben Youngs (Leicester Tigers, 28 caps)
1. Joe Marler (Harlequins, 5 caps)
2. Tom Youngs (Leicester Tigers, 4 caps)
3. Dan Cole (Leicester Tigers, 35 caps)
4. Joe Launchbury (London Wasps, 4 caps)
5. Geoff Parling (Leicester Tigers, 12 caps)
6. Tom Wood (Northampton Saints, 13 caps)
7. Chris Robshaw (Harlequins, capt, 12 caps)
8. Ben Morgan (Gloucester Rugby, 9 caps)
16. Dylan Hartley (Northampton Saints, 42 caps)
17. David Wilson (Bath Rugby, 22 caps)
18. Mako Vunipola (Saracens, 4 caps)
19. Courtney Lawes (Northampton Saints, 15 caps)
20. James Haskell (London Wasps, 45 caps)
21. Danny Care (Harlequins, 37 caps)
22. Toby Flood (Leicester Tigers, 53 caps)
23. David Strettle (Saracens, 12 caps)
Content courtesy of RFU