Ireland will take on Italy in Chicago on Saturday without Johnny Sexton, Rob Kearney and Peter O'Mahony.
Joe Schmidt has named the 26-man squad that departs today for the USA with the experienced trio rested, as expected, ahead of the upcoming Tests against Argentina, New Zealand and the USA next month.
Kearney, who has 86 caps, was replaced early in the second half of Leinster's Guinness Pro14 victory over Treviso on Saturday, while O'Mahony completed a bruising 80 minutes in Munster's win over Glasgow.
The flanker appeared to hurt his shoulder winning the last penalty, which Rory Scannell converted for a 25-24 win.
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Leinster back row Sean O'Brien, who played an hour of the game in Italy, has also been left at home, as have scrum-half Kieran Marmion and number 8 CJ Stander and captain Rory Best.
Ulster centre Will Addison has moved a step closer to his Test debut after his inclusion in the travelling party.
Former England Under-20s star Addison could now well make his senior international bow in the clash Soldier Field (8pm).
Leinster playmaker Ross Byrne has also edged closer to his Test bow in making the Chicago squad, with Joey Carbery possibly pencilled in to start at fly-half.
Addison left Sale for Ulster in the summer and has since earned rave reviews for a string of fine performances with the province.
Now the 26-year-old - who qualifies for Ireland through his mother - can push for his first Test cap, when Ireland take on Conor O'Shea's team.
Schmidt's decision to keep some senior players fresh for the Dublin encounters also means Ireland will have a new face as captain this weekend with Rhys Ruddock and Devin Toner among two in the frame.
Meanwhile, the Italy squad contains only one uncapped player in South African-born flanker lock Johan Meyer who qualifies after three years of playing for Zebre.
"We have a very difficult challenge against Ireland, who in the past created [problems] that we did not manage properly," head coach O'Shea said.
"But we will give 100 percent on the field. We are ambitious and we want to show our game. It will be important for us to put in a physically strong performance."
IRELAND
Forwards (15)
Finlay Bealham (Buccaneers/Connacht) 7
Tadhg Beirne (Munster) 2
Jack Conan (Old Belvedere/Leinster) 9
Sean Cronin (St. Mary's College/Leinster) 62
Tadhg Furlong (Clontarf/Leinster) 26
Dave Kilcoyne (UL Bohemians/Munster) 22
Jack McGrath (St. Mary's College/Leinster) 50
Jordi Murphy (Lansdowne/Ulster) 23
Andrew Porter (UCD/Leinster) 8
Quinn Roux (Galwegians/Connacht) 6
Rhys Ruddock (St Mary’s College/Leinster) 19
James Ryan (UCD/Leinster) 11
Niall Scannell (Dolphin/Munster) 9
Devin Toner (Lansdowne/Leinster) 60
Josh van der Flier (UCD/Leinster) 10
Backs (11)
Will Addison (Enniskillen/Ulster) *
Bundee Aki (Galwegians/Connacht) 9
Ross Byrne (UCD/Leinster) *
Joey Carbery (Clontarf/Munster) 12
Andrew Conway (Garryowen/Munster) 7
John Cooney (Terenure College/Ulster) 2
Jordan Larmour (St. Mary's College/Leinster) 6
Luke McGrath (UCD/Leinster) 6
Garry Ringrose (UCD/Leinster) 14
Jacob Stockdale (Ballynahinch/Ulster) 11
Darren Sweetnam (Cork Constitution/Munster) 2
* denotes uncapped player
