The 24-year-old has been called up in place of the injured Manu Tuilagi and he will partner Brad Barritt in a rejigged midfield for England's RBS 6 Nations opener at Twickenham.
Barritt will revert to the outside centre role he filled on his own Test debut in last year's Calcutta Cup win at Murrayfield, with Twelvetrees operating between him and Owen Farrell.
Tuilagi is expected to be fit for England's second appointment of the championship, away to Ireland a week on Sunday, but Twelvetrees is out to prove he is here to stay.
"You have to back yourself and what you can add to the team - otherwise there is no point being there," Twelvetrees said.
"I am very aware of Manu not being there but it is a great opportunity for me. Playing for England is a huge honour and I want to take every chance I am given.
"Players get their opportunities through injuries sometimes. I have to make the position my own.
"I have got to impose myself on the game and get my hands on the ball - otherwise there is no point being there.
"I want to show everyone what I can do.
"In a weird way I have always really enjoyed being nervous. You have to relish it. This is the biggest stage you can be on. I have always dreamed of it and I can't wait to run out."
The England management have long been fans of Twelvetrees, who offered what Gloucester director of rugby Nigel Davies described as a complete package of qualities at inside centre.
Twelvetrees is a powerful defender and a strong ball-carrier but he also offers a more natural kicking and passing game than Barritt.
Ultimately, Stuart Lancaster's selection choice for England's future midfield combinations may well come down to which of Twelvetrees or Barritt will partner Tuilagi in midfield.
"I coached him with the Saxons in the Churchill Cup and I could see then he had lots of potential and physicality," Lancaster said.
"I have always wanted ball-players in the back line, as well as people who can carry as well as pace and physicality.
"Billy has the opportunity to demonstrate that he has all three.
"I have every confidence in him going into the game.
"Sometimes opportunities present themselves in different ways. We know Manu is going to be fit for next week and we hope Billy puts a marker down this week and gives us another headache."
If Twelvetrees does succeed in cementing his place in the England midfield, his relationship with Farrell will become crucial - the modern day Jonny Wilkinson and Will Greenwood.
"We have been working on that relationship this week," Twelvetrees said.
"I looked up to those sort of players when I was growing up, whether it was Wilkinson and Mike Catt or Wilkinson and Greenwood.
"Sometimes those partnerships are under-estimated. You have to understand your fly-half and I think that will grow between me and Owen."
Twelvetrees made his Leicester debut in a Heineken Cup fixture against the Ospreys in 2009 at just 10 minutes' notice and emerged as man of the match.
Although he won Saxons recognition under Lancaster, he struggled for regular game-time and his summer move to Kingsholm has been key to his rise into the England ranks.
"Self-confidence and self-belief comes from playing regular rugby, game understanding and decisions under pressure," Lancaster said.
"He has an excellent kicking and passing game."
The only other change Lancaster has made to the England side that beat New Zealand in December was also injury-enforced, with Joe Marler replacing Alex Corbisiero at loosehead prop.
Tom Youngs has retained the hooker's jersey ahead of the more experienced Dylan Hartley, who missed the autumn series through injury.
Ben Youngs held off the challenge from Danny Care to keep the scrum-half position and Alex Goode returned from a shoulder injury in time to retain the full-back berth.
"We are happy to stick with the team that did so well against New Zealand," Lancaster said.
"We always had self-belief but what that win did was confirm to those outside the team that we have a group of players who will fight for the shirt.
"It was a tight call at hooker. Tom played very well in the autumn. Dylan comes back into the equation but I need to reward the player who is in the shirt.
"It's not a given but Tom has been outstanding since the New Zealand game for Leicester, both in the Premiership and in Europe."
The presence of Hartley, Care and Toby Flood among the replacements means that England's bench (230 caps) is more experienced that the starting team (191 caps).
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