Having yet to win a match in Group D, City are rock bottom with two points, yet victories over Real and in their final match away to group leaders Borussia Dortmund could see them squeeze into the last 16, depending on results elsewhere.
"It's always special to play against a club like Real Madrid. Personally, my connection with Atletico Madrid gives it an additional kick - but there's no difference in how much I want to win this match," Aguero told City's website.
"Never defeating Real when I was with Atletico was a real regret for me - Atletico haven't succeeded in beating them for many years - but I did get to score against them even if we never managed a win.
"Wednesday night will hopefully break that run for me."
It looks a tall order, but a 5-0 home victory against Aston Villa on Saturday, when Aguero netted twice, sent them top of the Premier League and raised spirits in time for the visit of Jose Mourinho's side who could go through if they better Ajax's result against Dortmund.
"We should never give up," the Argentine said. "Where there's a will, there's a way, right?
"Of course, it's harder now because we're not just relying on ourselves but also on the other teams' results.
"What we mustn't do is leave the pitch with any regrets and be content knowing that we have given our all. This club deserves nothing less and our supporters deserve as much, too."
France striker Karim Benzema, back after a thigh muscle injury, was in fine form in that victory, curling in a sweetly struck shot for Real's third goal and unselfishly setting up Mesut Ozil for their fourth.
"We don't like talking about individuals, but he [Benzema] had an outstanding game," former Real striker Emilio Butragueno, now a club director, told Spanish television.
"His movement in attack was fabulous and he scored a great goal," Butragueno added. "It was a delight to see him playing that way after his injury."
Mourinho, hoping to lead Real to the 10th European crown that has eluded them since 2002, also has Sami Khedira back after injury. The German international, who came on in the second half of the Bilbao game and netted Real's fifth, will likely rejoin Xabi Alonso in central midfield.
The 49-year-old Portuguese made his debut in Europe's elite club competition in February 2002 when he was in charge at Porto in a game they lost 1-0 to Real Madrid at the Bernabeu.
Probable teams:
