Holders Barca lead their Italian rivals by two points and their final match will be at home to minnows BATE Borisov meaning they can afford to draw with Milan and remain favourites to top the group.
The rossoneri will travel away to Czechs Viktoria Plzen in their last game so realistically need to beat the Spaniards to stand a chance of topping the group and avoiding potentially more difficult clashes in the second round.
When the sides met earlier in the competition Milan scored early and snatched a last gasp equaliser to earn a 2-2 draw in a game in which they were dominated.
But if history is anything to go by, this game could not be more evenly balanced.
They have met 12 times in the past winning four each with four matches ending in draws.
At the San Siro they have won twice each with one draw.
But there is no doubt that right now Barcelona are a notch above the Italians, who have won this competition seven times compared to four for the Catalans.
However, Milan’s last win came in 2007 while Barca have won it three times in the last six years.
And Milan’s Sweden forward Zlatan Ibrahimovic, who spent one year with Barca in 2009/10, is all too aware that his side are underdogs.
“It will be a very exciting, fantastic game,” Ibrahimovic told UEFA.com. “We will be playing against the best team in the world, without doubt.
“Even when I left the team, I knew I’d left the best team in the world. But for me and all the other parties involved I think the best solution was to leave the club.”
Although Ibrahimovic scored 22 goals in 42 games for Barca, he was widely seen as a disappointment and was replaced after just one year by David Villa.
However, he doesn’t feel he has anything to prove to his former employers, although, having missed the clash at the Camp Nou through injury, he’s keen to face his old side.
“For me, it’s important that you’re happy when you play. If you’re happy, it makes it easier for you,” he said.
“The way you feel off the pitch is the way you feel inside. I struggled there in the end, so the best thing was to move. I was a man; I stood up, we found a solution and I moved.
“I was looking forward to that match. I was training very hard but I got an injury the day before.
“I was disappointed but for me playing against a former team is nothing personal.
“Of course it’s emotional, a big game, but in the end it’s like any other game. There’s no need to over-hype it.”
For Barca centre-back Carles Puyol, however, this is the game his team has most been looking forward to.
“It’s the game we all want to play in. I’ve always liked Milan,” he said.
“It will be an important game and we hope that all goes well.
“We’ll go there with lots of enthusiasm, looking to play our football and trying to get a good result.
“Milan have lots of players who can make a difference so we’ll have to work really hard to try and win.”
Barca will be weakened by the absence of key midfielder Andres Iniesta but Milan are also without injured pair Antonio Cassano and Kevin Prince Boateng.
When the sides last met in the Champions League semi-finals in 2006, Barca won 1-0 at the San Siro to progress by the same score on aggregate before beating Arsenal in the final.
However, The most memorable clash between the pair came in the 1994 final when Milan produced one of the greatest performances of the competition’s history in winning 4-0.