Much of the attention will be on Mourinho and his opposite number as Villas-Boas is not only a former Chelsea manager, but also worked with his fellow Portuguese at Porto, Stamford Bridge and Inter Milan.
It will be the first time the pair have encountered each other in opposing dugouts after their relationship broke down in 2009.
If events on the touchline provide intrigue, so too will the team sheet submitted by Mourinho, who rather disingenuously suggested Tuesday night's Capital One Cup encounter at Swindon was a chance for fringe players to win a first-team place.
Mourinho has admitted he is uncertain of his best team, but whether Juan Mata has done enough to earn a place in the starting XI at White Hart Lane remains to be seen.
It is likely the Portuguese will field what he considers to be his best side against a Spurs squad he believes are one of five teams who could challenge the Blues for the Barclays Premier League title.
Fernando Torres, who scored one and made another at the County Ground to set up a fourth-round tie at Arsenal, could continue at striker, ahead of Samuel Eto'o and Demba Ba.
Gary Cahill is likely to remain at the heart of the defence, a position he has played in seven of Chelsea's eight matches this term; the only one he did not start was the loss at Everton.
Following successive losses at Goodison Park and to Basle in the Champions League, Cahill believes Chelsea have bounced back strongly.
"It was a tough week, especially when we lost back to back," Cahill told Chelsea TV.
"But we've responded really well. Two wins, two clean sheets. Happy days at the minute."
One of the reasons for Mata's omission is the new demands Mourinho is making of the World Cup-winning Spain playmaker.
He wants all of his players to defend and is deploying a higher line at the back.
Cahill added: "He really expects you to defend and know where to be. Not just the back four, but everybody when we lose the ball.
"I don't mind playing higher. It's difficult to play high against people with real, real pace.
"(But) I'm quite comfortable with playing high and I think the lads are."
One player who will not be in the Chelsea line-up is Marco van Ginkel.
The Holland midfielder has made just two appearances following his £8million move from Vitesse Arnhem and now faces six months of rehabilitation on a knee injury.
The 20-year-old underwent surgery on Thursday to repair a torn anterior cruciate ligament.
- Sports & Recreation
- Gary Cahill