Munster's influential lock Tadhg Beirne will miss Ireland's opening two Guinness Six Nations clashes due to a knee injury.
Ireland have called up Connacht lock Quinn Roux as cover, ahead of their Six Nations opener against England in Dublin on February 2.
Leinster's Adam Byrne has been added to the Irish contingent's training camp in Portugal, with Rob Kearney and Jack McGrath remaining with the province this week for extra game time.
Former Scarlets lock Beirne starred again as Munster bruised past Exeter 9-7 in Saturday's Champions Cup victory, though his injury loss is offset by Iain Henderson's return to action with Ulster.
"Following a scan Tadgh Beirne has been ruled out of the opening two rounds of the 2019 Guinness Six Nations with a knee injury," the Irish Rugby Football Union (IRFU) confirmed in a statement.
"Connacht's Quinn Roux has been called into the squad."
Ireland will start the defence of their Six Nations title by hosting England in Dublin, before taking on Scotland at Murrayfield a week later.
Beirne will now miss both encounters, but Ireland are expecting a better outlook for the likes of full-back Kearney, who is shaking off a minor thigh complaint.
"Adam Byrne will travel to Portugal as Andrew Conway picked up a knock against Exeter at the weekend and will be unable to train this week," continued the IRFU statement.
"Conway will be fully fit to train next week. Jack Conan will continue his treatment at Leinster this week and will be fully fit to train next week.
"Rob Kearney and Jack McGrath will remain with Leinster in order to gain game time in the Guinness PRO14 this weekend.
"All other players reporting niggles from the weekend will be managed by the Ireland medical team in Portugal."