Tigers coach Pat Howard intends making 15 changes from the side that crushed a weakened Bristol side 43-15 and claimed top spot at the west country club's expense.
Howard said: "I will change the whole 15 for the London Irish game. We will have Lewis Moody, Martin Corry, Andy Goode and Harry Ellis all out there.
"This is a very big period for us, and if we have done the right things medically and in terms of getting ourselves organised, then we will be okay."
The Bristol triumph ensured a flying start to Leicester's Christmas and New Year programme, which also features an appointment with Irish and a Welford Road clash against improving Saracens.
With more than half the regular league season still remaining, Howard has inevitably urged caution about Leicester's title prospects, but they are building ominously towards a serious tilt for silverware they last won in 2002.
He added: "There is a long way to go and we have got lots of big games coming up.
"Let's not read too much into it, but we are in the right position in the top four - that is where we want to be."
Wasps, in contrast, will slip out of the play-off zone if they lose at home to Gloucester on Tuesday and champions Sale Sharks beat Kingston Park hosts Newcastle.
The Londoners were left kicking themselves following an 8-6 defeat against lowly Northampton, and they could see their England prop Phil Vickery in disciplinary hot water after he was yellow-carded for stamping on Saints replacement Dylan Hartley.
Wasps rugby director Ian McGeechan admitted: "It was a game that got away. We ended up losing a game that we could have comfortably come away from with a win."
Gloucester, meanwhile, gained an evening off when their Kingsholm clash against Newcastle was postponed just 25 minutes before kick-off by referee Rob Debney due to fog which had engulfed the ground.
Sale's crippling injury list could show slight signs of abating when they travel to Newcastle on the back of an agonising 18-16 defeat against Bath.
Sharks rugby director Philippe Saint-Andre hopes to have scrum-half Richard Wigglesworth, hooker Sebastien Bruno, prop Stuart Turner and flanker Magnus Lund available after they all missed the west country trip.
The Premiership then continues with three more games on Wednesday. Bristol host Bath in a sold-out west country derby at Ashton Gate, Northampton travel to Saracens and Worcester entertain Harlequins.
And Bath head coach Steve Meehan will once again find himself facing a front-row conundrum after on-loan prop Jon Dawson lasted just 14 minutes of his debut against Sale.
Dawson, man-of-the-match in Cambridge's Varsity Match victory over Oxford two weeks ago, joined fellow Bath props Matt Stevens, Duncan Bell, David Flatman and Aaron Jarvis on the sidelines, although Meehan has completed a loan swoop for Gloucester's Terry Sigley.
Reflecting on the prop injury situation, Meehan said: "It is bizarre - I have never come across anything like it."
Northampton chairman Keith Barwell, meanwhile, is already well-advanced in terms of next season's plans, confirming the club are talking to "three current England internationals," although he has also dismissed speculation linking Saints' England hooker Steve Thompson with a move to French giants Toulouse.