After hanging on for a famous draw versus champions-elect Inter in midweek, the visitors will face a home side who have won only once in 11 matches.
The ongoing Indian summer being enjoyed by Euros-bound forward Goran Pandev continued in midweek, as the North Macedonia international's brace helped Genoa fight back twice against fellow bottom-half battlers Benevento.
A flurry of goals in the first 20 minutes saw the sides go in 2-2 at half-time, with neither able to net a winner in the second period - leaving the Grifone still glancing over their shoulder at the Serie A drop zone ahead of another crucial clash this weekend.
Though Genoa's run-in appears to read more favourably than those facing most of their rivals, they have now only won once in the past two months - that victory coming away at Serie B-bound Parma.
Just five points above 17th-placed Cagliari going into the league's 33rd round of 38, Davide Ballardini's side face another potential six-pointer against Spezia on Saturday and just a fifth win of a difficult campaign at Stadio Luigi Ferraris could prove invaluable.
Having celebrated his 100th game in charge of the club earlier this month - in his fourth spell there since the 2010-11 season - Ballardini has proved himself something of a fire-fighting specialist in avoiding demotion, but would now dearly love to start planning for next season in the top flight.
Spezia's last victory in this particular Ligurian derby dates back to 2006 - though the two sides have rarely clashed since then due to occupying different leagues.
As Genoa took the spoils in the first-ever Serie A meeting between the clubs late last year, Vincenzo Italiano's team will hope that belated revenge can not only give them local bragging rights, but spare them a nervous conclusion to a successful debut season.
The Bianconeri's remarkable 1-1 draw with league leaders Inter in midweek saw them inch five points above the bottom three heading into the final five games, and was achieved despite only registering one shot on goal and having just a third of the possession.
Only a rare Samir Handanovic error helped them take an unexpected lead at Stadio Alberto Picco on Wednesday, as Inter saw two 'goals' ruled out due to tight offside calls late on. Nonetheless, another point taken from the top two - after the memorable victory over Milan in February - keeps Italiano and company in contention to prolong their top-flight stay.
However, in their last five games played away from home, Spezia have been beaten on each occasion - with consecutive defeats against Bologna, Lazio, Atalanta, Juventus and Fiorentina skewering hopes of a remarkable top-half finish. They also have the fourth-worst rearguard in the league this term - with 60 goals now conceded: better only than Parma, Benevento and Crotone.
Having not repeated their previous result in any of their last eleven matches, the chances of the Aquilotti drawing in Genoa may be slim, but a point would be gratefully received by both sides.
Genoa head coach Davide Ballardini will be without the suspended Ivan Radovanovic for the visit of their local rivals, so veteran centre-back Cristian Zapata is expected to fill in alongside Domenico Criscito and Andrea Masiello in the hosts' three-man defence.
As ever, there is much competition for a place in the Grifone's front pairing, with much-admired Gianluca Scamacca set to be joined by any one of top scorer Mattia Destro, midweek saviour Goran Pandev - if fit to start twice in the space of a few days - or outside bet Eldor Shomurodov.
Spezia, meanwhile, take the short trip to Marassi with few injury concerns to contend with and may only rotate to spare legs ran ragged by Inter on Wednesday.
Top scorer M'Bala Nzola has been experiencing a goal drought of late, but is still favourite to start in the centre of the visitors' customary attacking trident. Daniele Verde may join him from out wide, with Kevin Agudelo's place most at risk from the former Roma man.
Genoa possible starting lineup:
Perin; Masiello, Zapata, Criscito; Biraschi, Strootman, Badelj, Zajc, Zappacosta; Destro, Scamacca
Spezia possible starting lineup:
Provedel; Ferrer, Erlic, Ismajli, Marchizza; Maggiore, Ricci, Pobega; Verde, Nzola, Farias
We say: Genoa 2-1 Spezia
Though they have delighted fans and neutrals alike with their refreshing approach to life in the Italian elite, Spezia's flaky defence has undermined much of their good work in the final third.
Genoa's striking options have tended to score in streaks, so perhaps Pandev or Destro can benefit from target-man Gianluca Scamacca's physical presence to strike on more than one occasion and seal just a second win in 12.