Manchester United have injury concerns over Anthony Martial and Marcus Rashford, so the 37-year-old has a chance to start.
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He could really do with a goal after enduring a poor start to the season for club and country.
He has played in all six of the Red Devils' league games but has only started against Brentford.
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Also, the former Real Madrid man has failed to score in the Premier League this season.
But he did manage to find the net in Man United's 2-0 win over FC Sheriff Tiraspol in the Europa League.
Ronaldo even struggled for Portugal over the international break, failing to score across two fixtures.
He did provide an assist in a 4-0 win over the Czech Republic, but his performance against Spain was heavily criticised.
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So Ronaldo could do with a goal and a big performance, and the Manchester derby might be the perfect opportunity.
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Ronaldo, as he does against most teams, boasts a strong record against City.
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He has played them 15 times across the Premier League, Champions League and FA Cup.
In those meetings, Ronaldo's side have won nine times, drawn twice and lost four.
The Manchester United icon has a one in three goalscoring record against the Citizens and has bagged against them in every competition, scoring five in total.
So you could say he is a due a goal against City to get his campaign underway.
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But in the Premier League, Ronaldo has only scored three times in 11 games against Man United's neighbours.
In fact, he only has one more goal than red cards in top-flight clashes between Man United and Man City.
And he has the same amount of yellow cards, so though his record looks good overall, in the Premier League, it isn't stellar.
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But Ten Hag's side head into the derby in form and looking dangerous.
The Red Devils won't have a lot of the ball against City, but that might suit them because they had less possession against Liverpool and Arsenal.
This counter-attacking style that Ten Hag has adopted in the big games might get the best from Ronaldo.
He is in the closing stages of his career, but he still has explosive pace over a short distance, and if Man United can provide the service, he could definitely get a goal and keep up his record against the Citizens.
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There are a lot of question marks over Ronaldo after a tumultuous summer, but these are the games he has thrived off in his career, so don't be surprised if he pops up with a goal or a big performance.