Last year’s New York City’s Barclays Center fight between the pair was hailed one of 2016’s best, and the rematch at Las Vegas’ MGM Grand promises to be the same.
Frampton has even said the two could meet again after the weekend bout – but if they do it will be in Belfast.
Friday sees the pair come face-to-face for the weigh-in.
It is scheduled for 3pm Vegas time, which is 11pm Northern Ireland time.
At stake is Frampton’s WBA world featherweight title – which he took from Santa Cruz in a majority decision last year having stepped up a weight division from super-bantamweight.
It cemented the Belfast boxer’s place in the sport’s history having become the first Northern Irish man to become a two-weight world champion.
The fight will take place on Saturday 29 January at the MGM Grand in Las Vegas, meaning it will start in the early hours of Sunday morning, probably around 4am our time.
The fight will be shown live on Sky Sports 1, with coverage starting at 1.00am.
Frampton: W23 KO14 L0 D0
Age: 29, height: 5’5″(165cm), reach: 62″ (157cm)
Santa Cruz: W32 KO18 L1 D1
Frampton hold the WBA world featherweight. The Northern Irishman is classed as the WBA’s ‘super’ champion, with Abner Mares holding the sanctioning body’s lesser featherweight belt.
What’s the odds?
Frampton to win: 4/6, for the KO 33/10 and on points 13/10, Santa Cruz 11/8 for the win, 5/1 for the KO and 5/1 on points and the tie 18/1
What other fights are on the Vegas bill ahead of headliner Frampton?
Dejan Zlaticanin vs Mikey Garcia
Lee Selby vs Jonathan Victor Barros
Josh Taylor vs Alfonso Olvera
Ivan Redkach vs Demond Brock
David Benavidez vs Sherali Mamajonov
Leduan Barthelemy vs Jesus Aguinaga
Wins, wins by knockout, losses, draws