Ulster outhalf Paddy Jackson will miss Ireland's entire Six Nations campaign with a dislocated elbow.
His club confirmed that Jackson requires surgery to repair the damage, and will be sidelined for up to 12 weeks.
Jackson's absence is a further blow to Ireland boss Joe Schmidt, who must do without Johnny Sexton for the tournament opener against Italy in Rome on Saturday 7 February.
Racing Metro fly-half Sexton is still in the middle of a 12-week stand down after suffering four concussions in a year, but should return in time to face England on 1 March.
Leinster's Ian Madigan and Munster's Ian Keatley will now contend the starting outhalf berth for Ireland's opening Six Nations clash in Rome.
"Paddy Jackson suffered a dislocated elbow in Saturday's defeat to Toulon at Stade Mayol," read an Ulster statement.
"A scan on Monday revealed that he has an unstable joint and that he will require surgery.
"He is expected to be out of rugby for between ten and 12 weeks."
Ulster centre Stuart Olding will also miss the Six Nations with elbow ligament damage that could see him out for three months.
Connacht confirmed a "low-grade ankle sprain" for centre Robbie Henshaw in their weekend European clash with Exeter.
The powerful midfielder could yet recover in time for Ireland's Six Nations opener, but will face a clear fitness battle.
The glut of injuries could see Ireland head coach Schmidt pair Ulster's utility back Jared Payne and Leinster centre Gordon D'Arcy for the upcoming trip to Rome.
"Stuart Olding also sustained an elbow injury against Toulon," Ulster confirmed in their statement.
"A scan has confirmed that he has significant ligament damage that will require surgery to repair. He is also expected to be out for between ten and 12 weeks."
Athlone-born Henshaw, who is viewed as the long-term successor to Brian O'Driscoll, has not suffered long-term damage, but will still have to work hard to face the Azzurri in Rome.
Connacht confirmed the 21-year-old will miss Saturday's European Challenge Cup trip to La Rochelle.
"Robbie Henshaw sustained a low-grade ankle sprain during the Exeter game," read a Connacht statement.
"The Ireland international will not recover in time for this week's game in France."
Long-term absentees Sean O'Brien and Cian Healy are closing in on returning to action, but Leinster have ruled out either facing Wasps in Champions Cup action this weekend.
O'Brien and Healy may yet struggle to feature in Ireland's Six Nations campaign despite nearing playing returns.
Lions flanker O'Brien underwent shoulder reconstruction after Ireland's 24-22 New Zealand defeat in November 2013.
The joint became infected and O'Brien went back under the knife in October.
Loosehead prop Healy is still recovering from a nasty hamstring tear suffered in September.