All the talk since Stuart Lancaster's team selection has centred around whether the former Leicester and Bedford playmaker can step up to the next level but Twelvetrees insists he has to embrace the pressure if he is to make the most of his surprise chance.
"You've got to enjoy it and you've got to relish it, otherwise there's no point being in this job," said Twelvetrees, who joins Harlequins prop Joe Marler as one of two injury-enforced changes from the starting side that saw off the All Blacks in December.
"I play the game because I love it. This is the biggest stage - I've always dreamed of this and I can't wait to run out there now.
"I'm very aware of Manu not being there but it's a great opportunity for me, and I just want to take the chance I've been given. You get your opportunity through injury sometimes, and you've got to make it your own.
"I've got to impose myself on the game and get my hands on the ball, otherwise there's no point being there. So I just want to get my hands on the ball and show everyone what I can do.
"Being in the side from the start, there's almost no excuses. I can plan ahead and work out what I'm going to do, and I'm looking forward to that side of things.
"It's very much over to me now: it's all on me how well I perform."
Twelvetrees only earned a full-time place in the EPS squad a month ago but he won't be lacking in confidence this weekend.
The 24-year-old quickly showed what he can do in training and is now determined to stamp his authority on the game at Twickenham.
"Making the full squad confirmed I'm worthy of a place - it officially makes you one of the best in England," added Twelvetrees.
"It really gave me the confidence to go out there and show, in a short space of time, what I've got and prove to the guys around me what I'm good at.
"I just thought, 'This is my time to really nail it down, and take my opportunity'.
"Being named in the squad is one thing, but I thought there's no point being in the squad if you're not going to play. I just wanted to train hard, get my hands on the ball, get stuck in and start communicating with the boys.
"We all want the same goal, winning for England, so getting adjusted quickly was important."