Ireland must bid to derail England's grand slam train without pivotal scrum-half Conor Murray, while boss Joe Schmidt has dropped lock Devin Toner for the first time.
British and Irish Lions star Murray has failed to recover from the "stinger" shoulder injury suffered in last week's 22-9 loss in Wales, so Kieran Marmion starts at scrum-half.
England will chase a second-successive RBS 6 Nations grand slam and world-record 19th consecutive win at the Aviva Stadium on Saturday, with Ireland opting for Iain Henderson's extra ballast at lock.
Head coach Schmidt has never before omitted Leinster lineout giant Toner for a pivotal Test, while Jared Payne also slots in at full-back with Rob Kearney missing through knee trouble.
"Conor Murray trained okay on Tuesday without contact," said Schmidt.
"We fitness tested him today and just felt that he wasn't going to be quite 100 per cent.
"Not that he couldn't function, just that once contact came back in and he got more bruising on top of bruising on that shoulder, we just felt that if we lost him early in the game, then you're vulnerable.
"It's a fantastic opportunity for Kieran Marmion.
"Iain Henderson came off the bench and did really well last week.
"So between Donnacha Ryan and Dev (Toner) we just wanted to give him an opportunity chance to start.
"It was a tight call as to how we jumbled that around, but Donnacha also played well last week. Not that Dev played badly but it was just trying to get that balance.
"So he's come in for that, and Rob Kearney has got a knee injury and is unavailable to be selected, hence Jared Payne has come in in his position.
"It probably won't be too long (for RK) but needs a bit of further investigation, and hopefully it's nothing too serious.
"He trained fully on Tuesday but was in a bit of discomfort afterwards, and he's just not fully fit to be selected."
Connacht scrum-half Marmion has 12 caps but just one start - against Canada in the autumn.
Former Leinster coach Schmidt admitted Ireland will miss Murray's "calm" and peerless direction in the heat of battle this weekend.
"You lose Conor's experience, 50-plus caps, you lose his calm; he's incredibly calm on the pitch," said Schmidt.
"He's a good foil for other players who are under pressure, because he very seldom looks like he's under pressure.
"You lose a defender who is incredibly good at organising other people and himself to make very good decisions, and then carry them through with positive action.
"His ability to control us and navigate us around the pitch, particularly with his kicking game, and the speed of his passing game.
"His experience will leave a hole for us, we've got a combined caps with Kieran Marmion and Luke McGrath of about a dozen, as opposed to about 140 that they have in their half-backs.
"And I guess the biggest thing is that what a fantastic opportunity to learn."
Munster lock Donnacha Ryan admitted surprise at Toner's omission, but vowed to forge a formidable partnership with Ulster's Henderson.
"Yeah, it's a tough call; it's a tough call across the board," said Ryan.
"I think we're all on par, we've all got different strengths and weaknesses.
"We're all adaptable to fit in to what the coaches need us to do for the particularly challenge we're facing .
"Iain and I, we just click back in, we both know the systems we have in place."