The two teams last met in the Championship in the 2011-12 campaign, but much has changed at both clubs since then, with Portsmouth now fighting to get out of League Two.
It will seem a long time ago for the club's supporters, but Portsmouth spent seven seasons in the Premier League from 2004, twice finishing in the top half and also winning the FA Cup in 2008.
It has been a downward spiral since 2010, however, with Pompey blighted by financial problems and dropping from the Championship to League Two in four seasons.
The glory days of European football seem a distant memory, but there is a feeling that the club can push for promotion from League Two this time around. Last term, they finished 16th in the table, but they started their campaign on Saturday with a confident 3-0 win over Dagenham & Redbridge.
Despite winning the FA Cup in 2008, the League Cup has not been a successful competition for the former Premier League side. They only reached the second round last season and have fallen at this stage in four of three of their last four attempts.
They did reach the quarter-finals in the 2009-10 season, but it came at a price as they were relegated from the Premier League in 20th position. The supporters have stayed with their team, however, and Fratton Park will be packed more times than not in the season ahead.
A cup run is secondary to success in the league, but it will hand a chance to a number of youngsters to impress. As expected, there has been a big turnaround this summer in terms of players, but only one that departed, Jed Wallace, actually brought money into the club.
Plymouth Argyle away next weekend is the next big game for Pompey, but night games at Fratton Park are always bouncing and Wednesday will be no different.
Recent form: LLLWL
Recent form (all competitions): DWWDW
Steve McClaren just fell short of leading Derby into the Premier League last season, but under new head coach Paul Clement, another promotion challenge is expected. Many have Derby's squad as the strongest in the Championship and that certainly brings pressure.
Like Portsmouth, Derby started their league season at the weekend, but they could not record all three points as Bolton Wanderers held the Rams to a goalless draw. It is expected to be another unpredictable and topsy-turvy Championship season, but Derby are among the favourites this term.
Not since the 2007-08 season have Derby competed in England's top flight, with seven straight seasons now spent in the Championship. Their push for promotion has impacted on their cup runs over the last few seasons, but they did reach the fifth round of the League Cup last term, eventually bowing out to Chelsea after overcoming the likes of Reading and Fulham.
Derby's home form in the league last season was strong, but they did drop points in 14 away games, while they have lost four of their last seven League Cup fixtures on the road.
It has been a solid summer in the transfer window, meanwhile, with the likes of Tom Ince, Andreas Weimann, Darren Bent, Chris Baird and Jason Shackell all arriving, and Will Hughes being kept out of the reach of a number of interested clubs. On paper, it is a squad that looks capable of challenging for promotion, but will the cup competitions be made a priority? That remains to be seen.
Recent form: WWWWL
Recent form (all competitions): WWDWD
With league matters the priority for Portsmouth, manager Paul Cook could ring the changes in a bid to keep his key players fresh in the early weeks.
As for Derby, head coach Clement has injury concerns over Hughes and Craig Bryson, who were both forced off in the clash with Bolton at the weekend.
Portsmouth possible starting lineup:
Jones; Davies, Webster, Burgess, Stevens; Hollands, Stockley, Doyle; McGurk, Evans, Chaplin
Derby County possible starting lineup:
Grant; Forsyth, Pearce, Baird, Shotton; Hendrick, Keogh; Ince, Thorne, Weimann; Bent
Head To Head
In total, these two teams have met on 85 occasions. Derby have won 38 of those matches, while Portsmouth have won 31 and the further 16 have ended level.
At Portsmouth, the hosts have won 22 of the 43 matches, with Derby victorious on 11 occasions.
The last time that the pair met was in the 2011-12 Championship season, when Derby won both fixtures, including a 2-1 victory at Fratton Park in April 2012.
We say: Portsmouth 0-2 Derby County
Both teams started their respective league campaigns last weekend and there is no question that both will see their next league fixture as more vital than this particular match.
With that in mind, Derby's squad is simply stronger than Portsmouth's and we believe that a second-string Rams will claim a comfortable 2-0 victory to advance into the second round.