Matt Doherty is out of Tottenham's clash with Manchester City on Saturday after contracting coronavirus on duty with Republic of Ireland.
The right-back returned a positive test taken after the UEFA Nations League defeat to Wales and must begin a 10-day period of isolation in line with UK government rules.
It means the summer signing from Wolves, who has impressed as part of Spurs' new-look side currently second in the Premier League, is also a doubt for the Europa League clash with Ludogorets the following Thursday.
Live Premier League
Doherty cannot come out of his confinement until Wednesday, November 25 - the day before Spurs face Ludogorets - having not trained with his team-mates.
Stoke's James McClean also returned a positive test while on duty with Republic of Ireland, so cannot play in their next two games against Huddersfield and Norwich on Saturday and next Tuesday respectively.
The pair both started in Sunday's 1-0 defeat, in which Tottenham players Gareth Bale, Ben Davies and Joe Rodon also played for Wales, and were then isolated from the rest of the group, who flew back to Dublin on Monday, after results on Sunday night.
Sky Sports Scores
Faster goal updates. Hundreds of teams and leagues. Free Premier League, EFL and Scottish highlights. Download the app now.
"The Football Association of Ireland can confirm Ireland defender Matt Doherty and forward James McClean have tested positive for Covid-19," a statement said. "The players have been isolated from the group as per Covid-19 protocols, and the HSE have been informed of this development.
"The rest of the staff and squad tested negative ahead of the flight back to Dublin this morning before the UEFA Nations League match against Bulgaria on Wednesday."
Live UEFA Nations League
The development represents a fresh headache for Republic of Ireland manager Stephen Kenny, who has already lost Callum Robinson and Alan Browne to positive tests this month.
Seamus Coleman, Enda Stevens and John Egan are also missing through injury, while James McCarthy had already withdrawn from the squad for family reasons.
And Kenny's resources were depleted further at the Cardiff City Stadium by Jeff Hendrick's red card and the booking that will see fellow midfielder Jayson Molumby join him on the suspension list against Bulgaria.
Shamrock Rovers pair Graham Burke and Aaron McEneff have been called up along with Millwall striker Troy Parrott and Peterborough's Jack Taylor.
Ireland need to avoid defeat at the Aviva Stadium to ensure they do not finish bottom of Group B4 and suffer relegation.