Pompey have played some of their best stuff in the cups this season, knocking Birmingham City and Queens Park Rangers out of this competition already and going two wins from two in the EFL Trophy group stages.
Saints, meanwhile, have already beaten Fulham in the EFL Cup but they enter this game on the back of a disappointing 3-1 defeat against Bournemouth on Friday night.
It has been a difficult start to the season for Portsmouth, with manager Kenny Jackett under real pressure heading into their most important game of the season to date.
Pompey's defeat to Wycombe Wanderers on Saturday took their record to just one win in seven League One games this season and they now sit just above the relegation zone.
Former Wolverhampton Wanderers boss Jackett made four changes for that game, with striker Oliver Hawkins deployed at centre-back, but the biggest blow was the red card picked up by Ellis Harrison, who was their top scorer so far this season with four goals.
Although Portsmouth usually set up in a 4-2-3-1, they may opt for a more conservative formation against the Saints that allows them to soak up the away side's high press and hit them on the counter with pace out wide.
Tuesday's game will be the 39th competitive meeting between the two South Coast rivals and midfielder Oriol Romeu has promised that Ralph Hasenhuttl's side will respond to their poor performance against Bournemouth with a win in the derby.
These two sides last met in the 2011-12 season, with both games in the Championship ending as draws, and one has to go all the way back to an FA Cup tie in January 1984 for Southampton's last away win against Pompey.
Although Austrian boss Hasenhuttl will be tempted to ring the changes after Friday's disappointing defeat that ended Saints' three-game unbeaten run in the top flight, he will be expected to field a strong side to try and secure an important victory.
He is, though, unlikely to alter his tried and trusted 4-2-2-2 formation, which will allow Southampton to dominate possession and make the most of their creative players like James Ward-Prowse and Danny Ings.
Portsmouth recent form (all competitions): WDWWDL
Southampton recent form (all competitions): LWWDWL
Exciting winger Moussa Djenepo is unlikely to be fit enough for Tuesday's game but, aside from him, Southampton have an almost fully-fit squad to choose from for the derby.
Danny Ings is expected to be favoured to Nathan Redmond up front to prevent a recurrence of the former Birmingham man's recent injury problems, while Stuart Armstrong could be preferred to Sofiane Boufal.
Portsmouth possible starting lineup:
MacGillivray; Walkes, Burgess, Naylor, Haunstrup; Close, McCrorie; Evans, Cannon, Curtis; Marquis
Southampton possible starting lineup:
McCarthy; Valery, Stephens, Yoshida, Bertrand; Romeu, Hojbjerg; Ward-Prowse, Armstrong; Ings, Adams
We say: Portsmouth 1-2 Southampton
Despite Pompey's recent struggles in the league, Kenny Jackett's side are likely to ramp up the intensity for what could be a full-blooded local derby, but Southampton should have too much quality in the attacking areas to be knocked out.
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