With Spurs' return to White Hart Lane beset by delays and Wembley unavailable, Mauricio Pochettino's team will meet Javi Gracia's side in Milton Keynes.
The choice of venue has certainly proven controversial with both sets of supporters and the decision to stage the tie at the home of League Two MK Dons could well have a major impact.
Spurs ended a three-match losing run with a 2-1 win against Brighton on Saturday and are chalked up as a 1/3 (1.34) chance with bet365 to win this one, while the odds compilers offer 7/2 (4.50) that penalties are required.
Watford have a poor recent record in this competition and the odds compilers are expecting another early exit for Gracia's men, with the Hornets available at a chunky 10/1 (11.0).
Dele Alli, who came through the ranks at MK Dons, and Moussa Sissoko could feature for Spurs in their quest for match fitness, whilst Harry Kane will surely be rested and Son Heung-Min may spearhead the attack.
Watford fielded a number of fringe players in the previous round so the likes of Ken Sema and Isaac Success are likely to be amongst the beneficiaries should Gracia shuffle his pack again here.
A tight tussle?
Watford have kept 10 clean sheets in their last 12 wins in this competition - including three extra-time victories.
Spurs, too, have kept a clean sheet in each of their last five victories in the EFL Cup and bet365 go 13/10 (2.30) that Pochettino's team win to nil on Wednesday.
An unusually low attendance is expected for this match and those who travel to Milton Keynes could well see a low-key game between two teams prioritising their participation in other competitions.
The 6/4 (2.50) quote, then, from bet365 for fewer than three goals to be scored could represent value for punters ahead of Wednesday's EFL Cup clash.
Odds correct at time of writing. Please gamble responsibly.