Bristol Rovers duo David Clarkson and Jim Paterson have been ruled out of Tuesday's tie.
The injured pair were set to miss the trip to Cheltenham on Saturday, which was postponed due to a waterlogged pitch, but they will not return against an Argyle side five points ahead of them in League Two.
Paterson has a hamstring tweak while Clarkson's ankle is still swollen and they will be joined in the stands by captain Garry Kenneth who will serve his one-game ban against Carl Fletcher's men.
Striker Tom Eaves has returned to parent club Bolton after his 93-day emergency loan deal expired on Saturday while right-back Danny Woodards looks set to be given the green light to feature after illness.
John Ward remains without long-term injury absentees Scott Bevan (wrist), club captain Matt Gill (knee) and Matt Harrold (knee) while defender Adam Virgo and midfielder Matt Lund are also out.
Pirates' boss John Ward turned down the director of football role at Home Park to become the new manager at the Memorial Ground two weeks ago.
Plymouth could be without their Boxing Day saviour Tyler Harvey after he came off on Saturday with a calf injury.
The 17-year-old youth product's second start for the club against Wycombe ended after 56 minutes when manager Carl Fletcher withdrew the striker, who scored Argyle's late equaliser at Torquay on Wednesday.
If Harvey does not make it then Warren Feeney or Rhys Griffiths could step into the side while midfielder Mark Molesley, who came on in the 1-0 defeat to the Chairboys, could earn a recall.
The Pilgrims have won just one of their last 14 games in all competitions and know defeat to Rovers could leave them just two points clear of the League Two relegation zone.