Care's absence robs him of an opportunity to go head-to-head with England's current first-choice scrum-half, Lee Dickson, less than a month before the Test series begins against South Africa.
Karl Dickson will now start for Harlequins, who finished top of the regular season table, in direct opposition to his younger brother.
Harlequins are also without wing Ugo Monye, but they do still feature seven of England's touring squad in their starting line-up.
Conor O'Shea's men were top of the Premiership table for 34 weeks, between September 17 and the final round of regular season matches, when they beat Sale at Edgeley Park.
But all that did was earn Harlequins a home semi-final.
O'Shea has not needed to remind his men that they have achieved nothing yet.
"To be top of the leaderboard from the word go and to take all that pressure is testament to the group they are," O'Shea said.
"There was an empty feeling in some ways after the Sale game on Saturday because we know we still face a massive task.
"But you don't expect things to be easy at this stage, do you?
"We can't wait. If we're clinical and we stop them when they have opportunities we'll win but it's going to be incredibly tight."
There is a perception that the eventual Premiership champions will come from the tie between Leicester and Saracens, two teams with hardened finals experience.
But O'Shea is quick to remind anyone that Harlequins beat Stade Francais and Munster en route to winning last year's Amlin Challenge Cup final.
"I think we've got more strings to our bow than we had 12 months ago," O'Shea said.
"Our scrum can be a dominant factor, as opposed to a survival factor.
"Our lineout and maul has become a weapon. We all know the way we want to play is with tempo and I think we can ask more questions of teams that way.
"It's the way the players enjoy playing it. As a management group we wouldn't put our name to any other style."
Harlequins only suffered four league defeats all season but one of them came to Northampton in January, when they were thumped 24-3 at Franklins Gardens.
But O'Shea insists that result will have no bearing on the semi-final.
"We had five games in 16 days which would have tested anybody," he said.
"It's irrelevant. We're pretty good when we're on the front foot and we know what this game is about. So do they."
Northampton were beaten semi-finalists last year but head into the game on the back of a bonus-point victory over Worcester and a run of four wins from their last five league games.
"It is going to be a very difficult game for us but I believe that we have the right mentality and players to be able to get the result we want," said Saints director of rugby Jim Mallinder
"We know we have the team to do well, now it is up to the players to show what they can do."
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