United, who have won 14 of their last 16 league games, are 12 points clear of second-placed champions Manchester City and can take another step towards an unprecedented 20th title while pushing Reading closer to the drop.
The visitors, who sacked manager Brian McDermott on Monday and are set to be in the hands of youth academy coach Eamonn Dolan on Saturday, have never won at Old Trafford and have only ever beaten Manchester United once - in an FA Cup match in 1927.
Reading have lost twice to United this season, 4-3 at home in the league and 2-1 away in the FA Cup and whoever takes over from McDermott, with ex-Swindon Town boss Paolo Di Canio the favourite, has a huge task on his hands to keep them up.
McDermott, who took Reading up last season and was named manager of the month for January, was sacked after his side lost a fourth successive league game to Aston Villa last weekend.
Di Canio, who was at the match, told British media this week: "I believe I am at a stage now where I am a Premier League or Championship (second tier) manager and want to go to an ambitious club with a winning mentality."
Reading will certainly need that to stay up as they are four points adrift of safety in 19th place with nine matches to play, level on 23 points with bottom side Queens Park Rangers who have improved their chances of late.
QPR will be looking for a third win in a row when they visit 17th-placed strugglers Villa also on Saturday.
Wigan Athletic, who surprisingly reached the FA Cup semi-finals for the first time when they won 3-0 at Everton on Saturday, are the other side in the drop zone and need a win at home to Newcastle United on Sunday.
Manchester United have had a bad week after being knocked out of the Champions League by Real Madrid and held to a 2-2 draw by Chelsea in the FA Cup after establishing a quick 2-0 lead at Old Trafford.
United, likely to be without injured winger Nani and possibly defender Phil Jones, will not want to slip up again against Reading, especially as Manchester City have their tails up after winning their last four league and cup games - scoring 12 goals and conceding none.
Five of those came without reply against Championship side Barnsley in the FA Cup last weekend when Carlos Tevez scored a hat-trick, but the Argentine is injured and may miss Saturday's trip to Everton.
David Moyes's team will be eager to put last weekend's defeat against Wigan out of their minds and pick up vital points in their hunt for European football next season.
However, they are likely to be without goalkeeper Tim Howard, who is suffering with two broken bones in his back.
Everton's dire weekend was completed when they slipped back from sixth to seventh in the league after arch-rivals Liverpool came from 2-1 down to beat Tottenham Hotspur 3-2 at Anfield on Sunday.
The result kept alive Liverpool's slim hopes of finishing in the top four and they visit lowly Southampton on Saturday.
However, London's Tottenham, Arsenal and Chelsea are still better-placed in the race to claim the other two Champions League spots, with United and City on course to finish one and two.
Tottenham lead the race in third place with 54 points, followed by Chelsea on 52 and Arsenal on 47, but Chelsea and Arsenal have played one match less than Spurs, who lost for the first time in 13 league games at Liverpool.
Spurs, who visit Inter Milan in the Europa League on Thursday holding a 3-0 first leg lead, will be at home to mid-table Fulham managed by former Spurs boss Martin Jol on Sunday, looking for an immediate return to winning league form.
Chelsea, who host Steaua Bucharest in the Europa League on Thursday, welcome London rivals West Ham United on Sunday while Arsenal, free of any other distractions after going out of the Champions League on Wednesday, face a tricky test at League Cup winners Swansea City.
Fifth-placed Arsenal can put some pressure on Chelsea and Spurs as they play 24 hours earlier than their rivals for the top-four although they will be without injured trio Jack Wilshere, Lukas Podolski and Bacary Sagna.
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