Damien Duff, Darron Gibson and Steven Reid are all out of the Republic of Ireland's World Cup qualifier against Italy at Croke Park on Saturday.
Duff's absence because of a calf strain is not a major surprise.
Reid's likely unavailability because of an Achilles injury has also been well signposted in recent days.
QPR's Martin Rowlands has been brought into the squad as cover but Gibson's withdrawal because of a groin injury is another blow for Giovanni Trapattoni.
Striker Caleb Folan had already been declared unavailable due to a hamstring injury.
The absence of midfielders Duff, Reid and Gibson makes Andy Reid's claims for a recall look all the more compelling.
However, Trapattoni opted not to call up any immediate replacements after Tuesday's withdrawals.
The unbeaten Republic take on Group Eight leaders Italy at Croke Park knowing a victory would move them to within one point of top spot, with one round of matches remaining.
Italy will secure their place in next year's finals if they avoid defeat.
Sunderland midfielder Reid again impressed for his club in Saturday's 2-2 draw against Manchester United.
However, the Dubliner has been out of favour for the Republic since being left out of the squad for the friendly against Poland last November.
Reports later surfaced of a late-night row between Trapattoni and the former Tottenham and Nottingham Forest player after the World Cup qualifier win over Georgia 13 months ago.
Reid has yet to have a single minute on the pitch in an international since the Italian's arrival in Ireland 17 months ago.
After Tuesday's withdrawals, Trapattoni insisted that the Sunderland man remained in his thoughts.
"I have seen him, I follow Andy Reid - I also follow Lee Carsley, Steven Reid.
"But, at this moment, we have a good squad of 25, 26, 27 players. I don't forget the others but, at the moment, the team is playing well and we are achieving results.
"Against Manchester United, he (Reid) played well - and he played better the game before.
"But, at the moment, he is playing wide left. He played against John O'Shea and played well.
"At this time, we have Aiden McGeady, we have Andy Keogh, we have Liam Lawrence - we have others in this position.
"At the moment, the players are playing well. But, in the future... I don't forget these players. I don't forget also Stephen Ireland. He is important."
Trapattoni criticised Fifa's decision last week that the upcoming World Cup play-offs would be seeded, which is likely to make the Republic's task more difficult - if the Irish are indeed involved in the games in November.
However, Trapattoni vowed that his team can be competitive against any opposition.
"For me, it is not important because big teams can lose.
"Now I am sure our team is confident and, in football, anything can happen.
"(But) In the future, Fifa and Uefa have to think about changing this rule.
"This draw must be open to give the same opportunity to everybody."