This time drawn together in the first round, both clubs will play their first competitive game of the 2024-25 campaign.
Match preview
Under the steady management of Alberto Gilardino, who led them to promotion from Serie B last year, Genoa secured a solid mid-table finish in Italy's top flight last season, placing 11th after a final-day win over Bologna.
Danish midfielder Morten Frendrup and Iceland international Albert Gudmundsson both played a major part in the Grifone's successful return to the big time, and despite being subject of serious interest from top-level teams around Europe, they remain in Liguria for now.
Genoa's impressive comeback was largely built on some fine form at Marassi, where they were only beaten five times in 2023-24, and they now begin a new campaign at their iconic home stadium.
After scoring six times in friendly wins over Venezia and Mantova late last month, Gilardino's men were beaten by Brescia at the start of August, before defeating Monaco 2-1 in their final friendly fixture.
While Italy's top eight teams will enter the Coppa Italia in the last 16, Genoa - who were eliminated by Lazio last term - still have two ties to negotiate before reaching that stage, and ahead of a tough league opener against reigning champions Inter Milan, they now meet Reggiana again.
It was Gudmundsson who scored an extra-time winner when the Grifone hosted their Emilian counterparts in last season's Coppa, as Reggiana bravely went out in the second round to Serie A opposition.
The Granata went on to miss out on the playoffs, finishing 11th in the final Serie B standings, and head coach Alessandro Nesta subsequently left for ambitious top-flight club Monza.
With the World Cup-winner departed, well-travelled manager William Viali has since been handed the reins, tasked with pushing for promotion to Calcio's elite level.
Reggiana's last Serie A appearance dates back to 1997, but a morale-boosting cup run could aid their hopes of returning to the promised land next spring.
After friendly losses to Fiorentina and Dinamo Tirana - both without scoring a goal - Viali saw his new team to beat modest Lentigione and Legnago Salus last week; however, they must step up significantly on Friday evening.
Genoa pre-season form:
Reggiana pre-season form:
Team News
Although most of their main men have been retained so far this summer, Genoa did lose first-choice goalkeeper Josep Martinez to Inter, so Atalanta BC loanee Pierluigi Gollini is set to vie with Nicola Leali to feature between the posts.
Vitinha, Koni De Winter and Morten Thorsby have all made their loan deals permanent, but Djed Spence has returned to parent club Tottenham Hotspur.
Uruguayan defender Alan Matturro was forced off by a shoulder injury during the recent friendly against Brescia and is set to miss out at Marassi, while Mexico's Johan Vasquez may only be fit for a place on the bench having just returned from extended leave.
Meanwhile, Genoa's Manolo Portanova thrived on loan at Reggiana last season and is reportedly wanted back by the Emilian club, but they will have to do without him on Friday.
Former Fiorentina striker Cedric Gondo should feature in the final third, while veteran midfielder Luca Cigarini - once of Atalanta and Cagliari - is also likely to start for the visitors.
Genoa possible starting lineup:
Leali; De Winter, Bani, Vogliacco; Messias, Frendrup, Badelj, Thorsby, Martin; Vitinha, Retegui
Reggiana possible starting lineup:
Bardi; Libutti, Meroni, Stramaccioni; Urso, Kabashi, Cigarini, Reinhart, Vergara; Vido, Gondo
We say: Genoa 3-0 Reggiana
A well-oiled machine under Alberto Gilardino - who stayed in post despite being linked with a move up the Serie A foodchain - Genoa should surely eliminate Reggiana for the second year running.