Fresh from victory over Chelsea in the FA Cup, the hosts welcome the Liga giants to the Etihad Stadium, with Gerardo Martino's side in imperious form at the weekend
In what is undoubtedly one of the most anticipated fixtures of the round of 16, Manuel Pellegrini's City welcomes 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 its impressive form in this season's Champions League, which saw it accumulate more points than Gerardo Martino's men in the group stage.
Despite finishing second in Group D behind holders Bayern Munich, City was able to beat the German champions and finish on 15 points - two more than Barca gained in Group H.
Pellegrini's side has failed to win just two of its 20 home games in all competitions this season and has conceded only 18 times in that run.
City has 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 organize. It was all about being focused and never losing concentration. Now I can drop into defense 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."
Despite City making the most of home comforts so far this season, Barca is likely to offer Pellegrini's charges a stern test when they visit, having reached at least the semifinal stage on its last six attempts.
Even with a draw against Milan and defeat to Ajax in the group stage, Barca topped its group by four points and remains on course for a treble - having already booked its 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 quarterfinals," 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.