The home team, meanwhile, are looking to secure a fourth top-half finish in the last five seasons.
After enduring a hugely disappointing season in which they finished 15th in the table last time out, Sampdoria have stabilised this campaign under the stewardship of Claudio Ranieri.
The former Leicester City manager, who guided the Foxes to a maiden Premier League title over five years ago now, has steered Sampdoria to ninth position in the table as things stand, with three wins from their last five matches hugely helping with that.
However, they were outclassed by Ranieri's former club Inter Milan, who were recently anointed Serie A champions for the first time since 2010, in a 5-1 defeat at the weekend.
Many expected Inter to suffer from a hangover after rightly taking part in wild celebrations in Milan throughout the week, but Antonio Conte's side were clearly fuelled on philosophical good spirits rather than alcoholic ones, with Alexis Sanchez's first-half brace helping them to a comfortable victory.
With a five-point cushion ahead of Udinese and Bologna in the bottom half, one more win should be enough to secure a top-half finish for Sampdoria, with a home match against Spezia representing an excellent opportunity of achieving that.
Few would have given Spezia much of a chance in terms of staying up in the club's first ever Serie A campaign, but their destiny remains in their own hands with only three matches of the season remaining.
Vincenzo Italiano, who guided the club to promotion via the playoffs last season, has fostered a side capable of competing against any team in the division, as shown by their recent 1-1 draw against Inter.
However, Spezia's form has significantly dipped in recent weeks, with that draw representing one of only two points they have gained in the last five matches.
Fortunately for Spezia, Benevento have been in freefall in recent months, with Filippo Inzaghi's side picking up only one point from their last six matches.
Spezia hold a three-point cushion over their fellow minnows, as well as a stronger head-to-head record, so they can actually afford one more loss than them between now and the end of the season and still survive.
Ranieri appears to be in the enviable position of having no known injury or suspension concerns ahead of Wednesday's visit of Spezia.
Given the short turnaround in fixtures, though, the 67-year-old may look to freshen up things with a few changes, particularly after such a disappointing performance against Inter on Saturday.
Spezia, meanwhile, will travel without Matteo Ricci after the midfielder picked up his fifth booking of the season against Napoli.
Sampdoria possible starting lineup:
Audero; Bereszynski, Tonelli, Yoshida, Augello; Candreva, Thorsby, Silva, Jankto; Quagliarella, Balde
Spezia possible starting lineup:
Provedel; Vignali, Ismajli, Chabot, Marchizza; Esteves, Acampora, Maggiore; Verde, Nzola, Gyasi
We say: Sampdoria 2-1 Spezia
We expect Sampdoria to be a little too strong for Spezia, who will undoubtedly put up a good fight as they always do under Italiano.
In reality, though, no outcome here would come as a surprise, especially with Spezia having more at stake to fight for on the day.