Cole wins his 36th cap, with Leicester Tigers team-mates Ben Youngs, Tom Youngs and Geoff Parling also included in the starting team and Toby Flood selected among the replacements.
Former Tigers centre Billy Twelvetrees makes his England debut in the No12 shirt.
England head coach Stuart Lancaster 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."
England (v Scotland, Saturday, 4pm)
15 Alex Goode (Saracens, 6 caps)
14 Chris Ashton (Saracens, 29 caps)
13 Brad Barritt (Saracens, 11 caps)
12 Billy Twelvetrees (Gloucester, 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, 9 caps)
16 Dylan Hartley (Northampton Saints, 42 caps)
17 David Wilson (Bath, 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)