The 2008 Cup winners are bottom of the Premier League and fighting a winding-up order over an unpaid tax bill.
The bitter rivals meet for the first time since Southampton were relegated from the Premier League in 2005 and Saturday's derby is given added piquancy because the hosts are recovering from near financial meltdown themselves.
After losing their Premier League status, Southampton spent four seasons in the Championship but were relegated last season and started this campaign in League One with a 10-point penalty for going into administration.
Despite that handicap, Southampton are comfortably placed in mid-table and would be challenging for a play-off place but for the points deduction.
Portsmouth, six points adrift at the bottom of the Premier League, like to regard themselves as the bigger of the two clubs.
Champions of England twice, in 1949 and 1950 while the Saints were in the Second Division, they won two of their four FA Cup finals in 1939 and again two seasons ago.
DELIGHTED COACH
Southampton though, have a modern stadium with 32,000 seats, 12,000 more than Portsmouth's Fratton Park ground, and can claim a rare FA Cup success as a Second Division side when they beat Manchester United in the 1976 final.
They have also beaten Portsmouth in all four FA Cup ties they have played since the first in 1905-06 and have booked a place at Wembley Stadium in March against Carlisle United in the final of the Football League Trophy for lower division sides.
Coach Alan Pardew said after they saw off Milton Keynes Dons on Tuesday he was delighted with his side, adding: "I will be very proud (to be at Wembley) because this is a big club.
"It was a special night, you only get that sort of atmosphere at a playoff game or a big FA Cup game which we have on Saturday. I am pleased for the fans, the owner and the chairman, because they deserve it.
FA Cup holders Chelsea should advance against Championship Cardiff City at Stamford Bridge, although they will be without their captain John Terry who has been given time off to sort out his off-field problems.
There are two all-Premier League clashes between Manchester City and Stoke City and Bolton Wanderers and Tottenham Hotspur, while Fulham should also go through against League Two Notts County, the lowest-ranked side left in the competition.
