Thursday night will be the first time ever Liverpool and Manchester United have ever met in a European competition; however it will be in the Europa League and not in the prestigious Champions League.
High off a 2-1 win against Crystal Palace on the weekend, the Reds will go into the game full of confidence after coming back from 1-0 down to win with 10-men and end a poor streak against the Eagles.
United go into the game after losing 1-0 to West Bromwich Albion but have won the last four games against their fierce rivals, including the last meeting in January.
The two sides meet in the last-16 of the competition with the first leg being held at Anfield before the return tie at Old Trafford next week.
Although it is in Europe's second-tier tournament, the match is one of the most highly anticipated the Europa League has ever seen and there is a lot is at stake for both of teams, who look unlikely of finishing inside the top four of the Premier League this season.
Reds boss Jürgen Klopp even went as far to say that this game is "the mother of all football games" as he talked up the importance of the competition to Liverpool and their season.
Both teams have struggled in the league this season, with neither currently in the top four, and both teams could miss out on Champions League next season, unless either team wins the Europa League or launches a late top four charge, which would also be reliant on rival teams slipping up in the coming weeks.
The Reds have lost twice to United this season so will be determined to beat them at least once this season and hope to gain an early advantage over the two legs.
Klopp could hand a start to Daniel Sturridge who has not featured at all over the last two games. He was left out of the squad against Manchester City, and did not come off the bench to feature against Crystal Palace.
Jon Flanagan will play no part as he is not registered to play in the Europa League which means Nathaniel Clyne is highly likely to return to the starting eleven, with Alberto Moreno the favourite to play at left-back.
Vice-captain James Milner is a major doubt for the game after he was sent home from training on Wednesday due to an illness.
For United, Jesse Lingard will have no part in the first-leg, as he is suspended. Long-term absentees Wayne Rooney, Ashley Young, Bastian Schweinsteiger, Luke Shaw and Phil Jones will also miss the game.
Manchester United have had another tough season, as they currently sit sixth in the league - just three points ahead of Klopp’s men, who have a game in hand.
Louis Van Gaal has come under a lot of criticism this season, and if reports are to be believed, he is due to be replaced at the end of the season.
After the amount the Red Devils have spent under him, a top four finish was the minimum that was required this season, but it seems they will miss out on this and their only hope for Champions League next season will be to win the Europa League.
Louis Van Gaal boasts a very impressive record against the Reds, having never lost a game against them since taking charge of United.
United have done the double over Liverpool this season, winning 3-1 and 1-0, they did the same last season as well, winning 3-0 and 2-1.
Klopp has also lost three times to the Dutchman, although he has won twice. The two managers have never drawn against each other.