With Manu Tuilagi ruled out with an ankle problem Twelvetrees has been given the nod as one of just two changes from the team that beat New Zealand 38-21 in the final autumn international.
Twelvetrees has been rewarded for his impressive Aviva Premiership form and will form a midfield partnership with Brad Barritt.
The only other change in the starting XV comes at loose-head prop with Harlequins' Joe Marler replacing the injured Alex Corbisiero.
There are three changes on the bench with Dylan Hartley, Toby Flood and David Strettle replacing David Paice, Freddie Burns and Jonathan Joseph.
Lancaster admitted the selection had been a tough one but called on his side to invoke the spirit of their All Blacks adventure in the Calcutta Cup.
"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," he said.
"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."
15. Alex Goode (Saracens)
14. Chris Ashton (Saracens)
13. Brad Barritt (Saracens)
12. Billy Twelvetrees (Gloucester)
11. Mike Brown (Harlequins)
10. Owen Farrell (Saracens)
9. Ben Youngs (Leicester Tigers)
1. Joe Marler (Harlequins)
2. Tom Youngs (Leicester Tigers)
3. Dan Cole (Leicester Tigers)
4. Joe Launchbury (Wasps)
5. Geoff Parling (Leicester Tigers)
6. Tom Wood (Northampton Saints)
7. Chris Robshaw (Harlequins) captain
8. Ben Morgan (Gloucester)
16. Dylan Hartley (Northampton Saints)
17. David Wilson (Bath)
18. Mako Vunipola (Saracens)
19. Courtney Lawes (Northampton Saints)
20. James Haskell (Wasps)
21. Danny Care (Harlequins)
22. Toby Flood (Leicester Tigers)
23. David Strettle (Saracens)