Meanwhile, the away team are looking to end a poor run of form which has seen them not win any of their last eight matches.
Twente were left empty-handed for the third game running as they suffered a 2-1 defeat at home against Utrecht on Sunday.
The Tukkers passed up an opportunity to move within four points of their opponents on the day, and they are now nine points adrift of the last European place.
With only four games left to play, Saturday's hosts have to win all their matches and also hope that results elsewhere go their way if they are to stand any chance of playing continental football next season.
However, the immediate concern is picking up a fourth straight win against their next visitors, with the most recent one a 2-0 triumph in September's reverse fixture.
Fortuna Sittard ended a run of three defeats in a row by claiming an emphatic 3-0 victory over ADO Den Haag on Sunday.
Zian Flemming set Sjors Ultee's men on their way with his ninth goal of the season five minutes before the interval, before Sebastian Polter and Tesfaldet Tekie struck after the restart to lay any doubts to rest.
The Fortunezen are now 12th in the Eredivisie table, but they are only separated from ninth-placed Twente on goal difference.
Saturday's visitors are set for their best points tally as well as their highest league finish since they were promoted in 2018, which is a huge testament to how far they have come.
Wout Brama is also expected to play no part as he remains sidelined with a leg injury through which he has missed each of the visitors' last three outings.
The home side are to set to be without first-choice goalkeeper Yanick van Osch, who continues to isolate after recently testing positive for coronavirus.
Piet Velthuizen was handed a rare start last time out, and the 34-year-old is in line to make back-to-back top-flight appearances for the first time in over two years.
Mickael Tirpan was subbed off in the closing stages of Fortuna's loss to Feyenoord earlier in the month, but he could make his comeback this weekend.
Fortuna Sittard possible starting lineup:
Velthuizen; Cox, Amiot, Angha, Rota; Hansson, Rienstra, Tekie, Semedo; Seuntjens, Flemming
FC Twente possible starting lineup:
Drommel; Smal, Pierie, Dumic, Ebuehi; Roemeratoe, Bosch, Zerrouki; Menig, Danilo, Van Leeuwen
We say: Fortuna Sittard 1-1 FC Twente
With the teams level on points, the game is a perfect opportunity for either side to steal a march on the other. We are predicting a close affair in this one and in the end, a point apiece for both sides.