The hosts are in the bottom three after losing both matches since returning to action, although they are only one point behind their equally out-of-form opponents.
Lecce appeared to have turned a corner in their battle to avoid a drop when winning three games on the spin in February, but they have lost four out of four since then.
That run includes a 7-2 thrashing at the hands of high-scoring Atalanta BC immediately before the three-month hiatus when Duvan Zapata helped himself to a hat-trick.
The Giallorossi have shipped 19 goals in those four matches. At home, they have conceded 11 goals in their last two - only Foggia in 1992 have let in more in back-to-back games.
It is clear what area Fabio Liverani needs to work on with his players, then, ahead of what is a truly massive game for Lecce.
Sampdoria have themselves lost three in a row, all by the same 2-1 scoreline, since returning to action earlier this month.
The Blucerchiati spent the first few months of the season in the relegation zone and are at serious risk of dropping back into the bottom three should they lose on Wednesday.
Only Genoa sit between Lecce and 16th-place Sampdoria, rightly seeing this contest labelled as a relegation six-pointer.
The good news for Sampdoria is that they are unbeaten away to Lecce since 1991, with the hosts picking up just one point in their last seven home meetings.
That includes a 1-1 draw in the reverse fixture eight months ago - a result that would just about suit Claudio Ranieri's men more if it was to be repeated on Wednesday.
Sampdoria have the tougher of the remaining games, however, with matches against Atalanta, Juventus and Milan to come, so they will be keen to distance themselves from the dropzone.
Lecce's Serie A form: WWLLLL
Sampdoria's Serie A form: WLWLLL
Lecce are without defender Fabio Lucioni for this massive showdown following his dismissal 30 minutes into the 4-0 loss to Juventus on Friday.
Midfielder Marco Mancosu has been directly involved in three of Lecce's last five home goals, scoring two and assisting one.
As for the visitors, experienced attacker Fabio Quagliarella remains sidelined in what is a big blow to their survival hopes.
Wednesday's match will be a special occasion for Sampdoria midfielder Andrea Bertolacci, having played 37 games and scored six goals in Serie A for Lecce between 2010 and 2012.
Lecce possible starting lineup:
Gabriel; Rispoli, Donati, Rossettini, Paz, Vera; Tachtsidis, Petriccione, Mancosu; Shakhov, Falco
Sampdoria possible starting lineup:
Audero; Bereszynski, Tonelli, Colley, Murru; Dapaoli, Vieira, Ekdal, Linetty; Gumina, Gabbiadini
We say: Lecce 2-2 Sampdoria
Lecce have lost their last four Serie A games by an aggregate scoreline of 19-3. They have not lost five in a row since 2005 and, given the form of opponents Sampdoria, we can see them at least ending that losing run on Wednesday.