Southampton will be without Danny Fox.
The defender is cup-tied having played in the competition for Burnley before completing his move to Saints last month.
With Dan Harding also likely to miss out due to a knee injury, Ryan Dickson could be handed a rare start at left-back.
Manager Nigel Adkins will make further changes following Sunday's 4-1 win over Birmingham with back-up goalkeeper Bartosz Bialkowski set for another run-out in place of Kelvin Davis.
Aaron Martin, Lee Holmes, Morgan Schneiderlin, Richard Chaplow, Steve de Ridder and Jonathan Forte could all be in the starting line-up.
Defenders Dan Seaborne (head) and Radhi Jaidi (knee) and striker Lee Barnard (ankle) are still on the sidelines.
Preston manager Phil Brown is expected to shuffle his pack as his in-form side look to make it seven successive wins.
The Lillywhites team which beat Charlton in the last round featured several youngsters, including Seanan Clucas, Danny Mayor and Juvhel Tsoumou, and they could start again.
Brown could also give Jamaican international Keammar Daley his North End debut.
Defenders Daniel Devine and Steven Smith are back in full training and in contention.
Goalkeeper Iain Turner is nearing a return from the toe injury which he sustained against Yeovil, but Andreas Arestidou is expected to retain his place.
Brown's decision to rotate his squad could also provide Adam Barton with an opportunity to impress.