The Hatters currently find themselves in 14th place in the Championship, seven points off the play-offs and eleven points clear of the relegation zone.
Veljko Paunovic's Reading has a significantly better record in the FA Cup in recent seasons, reaching the semi-final in 2015.
The Royals currently find themselves in fifth place in the Championship, three points off the automatic places.
Both sides are expected to rotate as they focus on their aspirations in the league.
Luton will be without Luke Berry and Eunan O'Kane, and will also be without Joe Morrell.
Reading will be without Yakou Meite and Liam Moore, whilst Andy Yiadom, Felipe Araruna, and Lewis Gibson are also out.
Sluga; Osho, Lockyer, Bradley, Norrington-Davies, Rea, Cornick, Berry, Dewsbury-Hall, Clark, Collins.
Southwood; Esteves, Dorsett, McIntyre, Bristow, Watson, Tetek, Aluko, Onen, Baldock, Puscas.
Ones to watch
Osho will be making his debut if he does play, and it will be against his former club. The 22-year-old was released by reading in the summer after failing to agree on a new contract at the club and joined Luton in October. He immediately joined National League side Yeovil Town on loan for the next month to build up fitness, but is now back in Luton and will now look to show the Royals what they missed out on.
Reading's backup goalkeeper this season behind Rafael, the 23-year-old has been patiently waiting for his opportunity after not playing since September. There were calls for him to take Rafael's place after the Brazilian went into a bad patch of form, so reading's academy product will be using the game to stake a claim to get some chances in the league.
These two sides have already met twice this season, the last time being on Boxing Day when Reading won 2-1 through goals from Alfa Semedo and Tom McIntyre. They also met in the Carabao Cup in September, when a Jordan Clark header set up a tie with Manchester United for Luton.
How to watch
this match will kick-off at 12:00 pm on Saturday, January 9, and is available to watch on BT Sport Extra 6.