This will mark a return to the British Isles for new Roma boss Claudio Ranieri, whose stint in charge of Leicester City saw them pip Spurs to the title in 2016.
Match preview
It is almost certain that no team will record a more remarkable scoreline across Europe this season than Spurs' 4-0 thrashing over Man City on Saturday - Pep Guardiola's worst home defeat of his managerial career.
Ange Postecoglou's side are now comfortably the top scorers in the Premier League, and only Liverpool and Man City have conceded fewer, but with just three clean sheets in the league, that suggests why they have dropped so many points.
Spurs are still down in sixth, three points off the top four, with too many disappointing recent results restricting them from moving further up the standings.
The international break came at the perfect time, because Spurs' two performances prior to it were woeful, handing Ipswich Town their first Premier League win in over 20 years, and being very lucky to leave Istanbul with a 3-2 loss against a Galatasaray side that could have scored seven or eight.
That result ended their 100% record in Europe, and saw them drop to seventh, but they will fancy their chances of moving back up the standings here, considering they have won seven in a row at home in the Europa League without conceding - scoring 19.
This will be their first ever meeting with Roma, and the home side will hope that they can continue their fine record at home to Italian clubs, because Spurs have only lost once in 10 previous meetings.
The Europa League has not provided many fruitful results against clubs from Italy for Spurs though, winning just two of their eight, and Roma will hope they can extend that underwhelming run, while also arresting a woeful stretch of results of their own.
Now on their third permanent manager of the season already, the Romanisti have witnessed a dismal start to the campaign across both competitions domestically and on the continent.
Daniele De Rossi was dismissed within four games, and Ivan Juric lasted just 12, reminiscent of his spell at Genoa in 2018 when he won none of his eight games in charge and was sacked after two months.
At 73, Ranieri has been persuaded to come out of retirement to take over at a club where he is loved by the supporters, so owners the Friedkin Group must be wary of upsetting the supporters again with the new manager like they did when they sacked De Rossi.
Ranieri was unable to end their recent losing run, as a 1-0 defeat at league leaders Napoli saw that streak extended to three matches, dropping to 12th, just three points from trouble.
A 1-1 draw with Union SG on matchday four keeps them down in 20th in the UEL standings, with their only win so far coming by a solitary goal against Dynamo Kyiv, a club without a goal or a point as of yet in the Europa League.
Roma's matches only get tougher too, so they are slightly up against it to ensure they remain in the top 24, considering they will face Spurs and AZ Alkmaar away, and Braga and Eintracht Frankfurt at home.
Tottenham Hotspur Europa League form:
W
W
W
L
Tottenham Hotspur form (all competitions):
L
W
W
L
L
W
Roma Europa League form:
D
L
W
D
Roma form (all competitions):
L
W
L
D
L
L
Team News
Postecoglou's defensive options were decimated even further in the week, when it was revealed Guglielmo Vicario had undergone surgery on a broken ankle, sidelining him for the foreseeable future.
Spurs are already without their two first-choice centre-backs Cristian Romero and Micky van de Ven, so Radu Dragusin and Ben Davies are set to start again after impressing against Man City.
Will Lankshear and Mikey Moore have been handed opportunities in Europe so far, but neither will feature, with Lankshear suspended following his red card against Galatasaray and Moore currently wiped out with a virus.
Rodrigo Bentancur will almost certainly start to ensure he maintains his match fitness, as his seven-game ban is only for domestic fixtures.
After playing 3-4-3 under Juric, Ranieri opted to revert to a more old-fashioned 4-4-2 in the Napoli defeat, despite making very few changes to the personnel.
Lorenzo Pellegrini returned from injury to replace Matias Soule in the only change from Juric's final game, while Paulo Dybala was only fit enough for the bench.
Mario Hermoso and Alexis Saelemaekers are both closing in on a return to the first team, but Uzbek international Eldor Shomurodov is a confirmed absentee with a muscle problem.
Tottenham Hotspur possible starting lineup:
Forster; Spence, Dragusin, Davies, Gray; Sarr, Bentancur, Bergvall; Johnson, Solanke, Werner
Roma possible starting lineup:
Svilar; Celik, Mancini, Hummels, Angelino; Soule, Baldanzi, Cristante, Zalewski; Dybala, Dovbyk
We say: Tottenham Hotspur 2-0 Roma
Roma are in dire straits, and have a woeful record in England, winning just one of their 23 games in the country, and none of the last 15 since winning at Liverpool in 2001, and current form offers very little to suggest they could end that here.