Having lost each of the last three meetings between the sides, the Men in Red also head into the midweek clash looking to get one over the visitors and get their season up and running.
Match preview
Chicago Fire's poor early-season form continued on Sunday as they could only salvage a 1-1 draw against DC United when the sides met at the Audi Field Stadium.
Swedish defender Christopher McVey put the home side ahead in the 20th minute but former Los Angeles FC man Kellyn Acosta struck in the 53rd minute to force a share of the spoils.
Frank Klopas's men have now failed to taste victory in any of their last seven matches, losing five and claiming two draws since scraping a 2-1 win over Houston Dynamo at home on April 7.
Chicago Fire's slow start to the season has been owing to their struggles in front of goal, where they currently hold the second-poorest record in MLS, having scored just 15 goals so far — only rock-bottom New England Revolution (9) have scored fewer.
With 11 points from 15 matches, the Men in Red are currently 14th in the Western Conference standings, just four points above New England Revolution but could move into 12th place with all three points on Wednesday.
Orlando City, on the other hand, continue to struggle for results on home turf as they fell to a 2-0 defeat against Columbus Crew when the sides met at the Exploria Stadium on Sunday.
Uruguayan striker Diego Rossi continued his fine run of form in front of goal as he converted his penalty on the stroke of half time before netting his second of the game in the 61st minute to hand the Crew a comfortable victory.
Orlando City have now failed to win their last five home matches, losing three and claiming two draws since picking up a 2-0 victory over Austin FC on March 24 courtesy of goals from Jack Lynn and Nicolas Lodeiro.
Oscar Pareja's men have now lost six of their 14 MLS matches while claiming four wins and four draws to collect 16 points and sit 10th in the Eastern Conference table, level on points with 11th-placed Nashville.
While Orlando have struggled to get going at home, they head into Wednesday's game unbeaten in each of their last four away matches, picking up three wins and one draw since March's 2-0 defeat against Atlanta United.
Chicago Fire Major League Soccer form:
D
L
L
L
L
D
Orlando City Major League Soccer form:
L
L
W
D
W
L
Team News
Chicago Fire will take to the pitch without defender Allan Arigoni, who is currently suspended after crossing the yellow card threshold with his booking against DC United on Sunday.
In his absence, Arnaud Souquet should come into the form, teaming up with Carlos Teran, Rafael Czichos and Andrew Gutman in the back four, with Chris Brady retaining his role between the sticks.
On the injury front, Klopas will be unable to call upon the defensive duo of former Silkeborg man Tobias Salquist and 28-year-old Chase Gasper, who continue their spells on the sidelines.
American striker Duncan McGuire was a notable absentee in Orlando's weekend defeat against the Crew and the 23-year-old is a major doubt for Wednesday's game.
He is joined on the Lions' injury table by Michael Halliday and teenage defender Tahir Reid-Brown, who are currently recuperating from knee and thigh injuries respectively.
Chicago Fire possible starting lineup:
Brady; Souquet, Teran, Czichos, Gutman; Navarro, Pineda; Barlow, Gutierrez, Acosta; Cuypers
Orlando City possible starting lineup:
Gallese; Thorhallsson, Brekalo, Schlegel; Lodeiro, Martins, Cartagena, Angulo; Torres, Muriel, Enrique
We say: Chicago Fire 1-2 Orlando City
While Chicago Fire will be looking to find their feet, they face the stern challenge of taking on an Orlando side who have been rock-solid on the road in recent weeks. The Lions have won their last three games versus the home side and we see them extending this run on Wednesday.