In what is undoubtedly one of the most anticipated fixtures of the round of 16, Manuel Pellegrini's City welcome the Spanish champions to the Etihad Stadium for the first leg.
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With both teams firmly in contention for their respective domestic titles, City will be particularly buoyed by their impressive form in this season's Champions League, which saw them accumulate more points than Gerardo Martino's men in the group stage.
Despite finishing second in Group D behind holders Bayern Munich, City were able to beat the German champions and finish on 15 points - two more than Barca gained in Group H.
Pellegrini's side have failed to win just two of their 20 home games in all competitions this season and have conceded only 18 times in that run.
City have scored at least four goals in 12 of those matches, with former Barca midfielder Yaya Toure enjoying his more advanced role under Pellegrini.
"At Barcelona it was my job to hold and organise. It was all about being focused and never losing concentration. Now I can drop into defence or join the attack," he told Uefa.com.
"I was limited to playing in the middle at Barcelona. I like playing in England because it's an open league and very fast-paced.
"The first two campaigns were difficult, but now everything is going well."
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Even with a draw against Milan and defeat to Ajax in the group stage, Barca topped their group by four points and remain on course for a treble - having already booked their place in the Copa del Rey final.
With Tuesday's opponents having averaged three goals a game during their group campaign, Martino remains confident in his side after Saturday's comprehensive victory over Rayo.
"We're on form coming into the match against City, this is the perfect moment to try to qualify for the quarter-finals," he told Barca's official website.
"Most of the players are playing really well."
Sergio Aguero is likely to miss out for City but Fernandinho could return, while Martino has no injury concerns.