Iain Henderson has suffered a finger injury that will dent Ireland's resources at lock for the start of their Six Nations defence.
Ulster lock Henderson's new blow comes on the same day Munster second row Tadhg Beirne was ruled out of Ireland's first two Six Nations encounters due to a knee problem.
Ireland still have James Ryan, Devin Toner, Ultan Dillane and Quinn Roux in the ranks, but both Henderson and Beirne would have been pressing hard for action.
Henderson had only just returned from a five-week lay-off due to a thumb problem for Saturday's 14-13 Champions Cup win at Leicester, and picked up a fresh injury in that Welford Road victory.
"Iain Henderson suffered a finger injury that is likely to keep him sidelined for several weeks," Ulster confirmed in a statement.
"This fresh injury is unrelated to his recently injured thumb."
British and Irish Lions lock Henderson's absence will be a clear blow to head coach Joe Schmidt, especially off the back of in-form Munster second row Beirne's injury too.
Ireland confirmed on Monday morning that Beirne will miss the opening Six Nations matches, against England and Scotland, owing to a knee complaint.
Ireland called up Connacht's Roux as cover, ahead of their opening Six Nations clash 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 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."
