The hosts thrashed their opponents 3-0 and gained a measure of revenge for defeat in their World Cup play-off match.
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But Steve Clarke's side were beaten 3-0 by the Boys in Green in the reverse fixture, so this will be a tough test.
Stephen Kenny's men haven't played any football since June but have managed draws against Ukraine and Belgium this year as well as the win over Scotland.
They also boast a decent record over their opponents and lost only one of the last five meetings between the sides.
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So this could be an intriguing clash, but Scotland must have some confidence going into this one.
Scotland v Republic of Ireland: Date and how to follow
This UEFA Nations League clash will take place on Saturday, September 24.
Kick-off Hampden Park is scheduled for 7:45pm.
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The match will be broadcast on Premier Sports One, while subscribers can watch via the website or Premier Player app.
Fans can sign up to Premier Sports for £9.99 per month.
talkSPORT will have updates throughout the evening and talkSPORT.com will have a live blog.
To tune in to talkSPORT or talkSPORT 2 through the website, click HERE for the live stream. You can also listen via the talkSPORT app, on DAB digital radio, through your smart speaker and on 1089 or 1053 AM.
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Scotland v Republic of Ireland: Team news
Everton's Nathan Patterson will miss out after he was stretchered off during the Ukraine game with what looked to be an ankle problem.
Celtic's David Turnbull has also withdrawn from the squad with injury and Josh Doig and Declan Gallagher have been called up.
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Andrew Robertson, Liam Cooper, Grant Hanley, Jacob Brown and Jon McLaughlin are all missing as well.
Meanwhile, the visitors are without Caiomhin Kelleher and Darragh Lenihan.
Gavin Bazunu and John Egan are expected to take their places, while Matt Doherty could start despite his lack of minutes for Tottenham Hotspur.
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Scotland v Republic of Ireland: What has been said?
Steve Clarke: "We know only too well from our experiences in the summer how difficult the game's going to be and we have to be ready for everything Ireland throw at us.
"We need to combat their strengths and make sure we play to our maximum and show our qualities. We showed improved performance against Ukraine in midweek from what we did in the summer and the idea is to replicate that again."
Stephen Kenny: "We want to finish [the campaign] strong.
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"It is a big game. A great game. Ireland against Scotland in the Nations League, in Hampden Park, a famous venue, we're delighted to be going there.
"Scotland qualified for the European championships previously, a lot of their players are playing in the high end of the Premier League."
Scotland v Republic of Ireland: Match facts
The reverse fixture between these two sides was won 3-0 by the Republic of Ireland in Dublin back in June, with goals from Alan Browne, Troy Parrott and Michael Obafemi earning their nation their largest ever margin of victory in this fixture.
Scotland have won one of their last five matches against the Republic of Ireland (D1 L3), though it was the last time they hosted this fixture, back in November 2014 in a Euro 2016 qualifying match.
Republic of Ireland's only victory from 14 UEFA Nations League matches came against Scotland in June (otherwise D6 L7). Republic of Ireland scored as many goals in that game as they have managed in their other 13 matches combined in the competition (3).
After winning just one of their first 16 matches under Stephen Kenny (D8 L7), Republic of Ireland have since won five of their last 10 matches under his tutelage (D3 L2).
Scotland are unbeaten in all six of their home matches in the UEFA Nations League (W5 D1), keeping four clean sheets in this run. Only Germany and Italy (seven games each) have played more on home soil without losing in the competition.
Republic of Ireland's 20-year-old forward Troy Parrott has scored four goals in 15 appearances for the national team. Only two players have ever scored five times before turning 21 for the Boys in Green - Robbie Keane (7) and David Connolly (6).
John McGinn has been involved in 13 goals in his 16 home starts for Scotland under manager Steve Clarke (10 goals, 3 assists), although he's yet to score on home soil in the UEFA Nations League.
Since Stephen Kenny took over in September 2020, Callum Robinson has scored the most goals (6), taken the most shots (41) and registered the most shots on target (16) of any Republic of Ireland player. Central defender Shane Duffy is either second or joint-second for each (4 goals, 26 shots, 9 shots on target).
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