Toronto Mayor Rob Ford is leading a delegation of about 70 business leaders on the three-day trip to Chicago.
The mayor says he hopes to rekindle the business relationship between the two cities.
Prior to his departure, Ford said he was "excited" about the trip, which he hoped would yield dividends for both cities.
"This is all about jobs, jobs and more jobs," Ford told reporters on Tuesday morning.
The Team Toronto trade mission leaves Tuesday afternoon and includes business leaders from across the city.
The Toronto Board of Trade's Carol Wilding says "there are tangible opportunities. We've got Kraft and Wrigley who are headquartered in Chicago, but also have large operations here in Toronto. What could that look like in other sectors?"
Mike Williams is the city's head of economic development. He says the cities share a 20-year relationship that's recently focused on culture but will now shift to business.
"We need to wave our flag and say 'Listen, we exist. We're not very far away from you. We're a huge market," he said.
The trip also comes at a time when Mayor Ford has faced a torrent of criticism over allegedly using office staff to help coach his football team.
The trip's co-chair Porter airline president Robert Deluce believes it won't interfere.
"It doesn't bother me at all," Deluce said. "It's noise in the background. What I'm concerned about are the results."
The Mayor of Chicago, Rahm Emanuel, is also dealing with controversy.
He was President Obama's chief of staff, but as mayor he's been dealing with Chicago's first public teacher's strike in a generation.
The two mayors are scheduled to meet on Wednesday afternoon.