Police and emergency workers responded at about 9:30 a.m. to the Piper Jaffray building construction site on Nicollet Mall.
CBS stations WCCO-TV and WCCO Radio reported two people were killed. It was unclear if anyone else was injured.
A witness told WCCO-TV that a large bin containing tools fell from a crane and broke through at least three floors.
The street was blocked off and many ambulances were on the scene.
"We sort of saw the aftermath and the police and the sirens," said Scott Hagen, a supervisor at a Barnes and Noble store across the street.
"We see the big hole going through all the floors, going from the top floor all the way through all the floors. It looks as if something may have crashed through," Hagen said.
Hagen said the site has been busy with workers since construction began this summer.
Piper Jaffray Inc. broke ground in July on a new 30-story office tower.
Ryan Companies U.S. Inc. is the developer of the project. Piper Jaffray is to occupy about half the tower as the anchor tenant. The building was scheduled for completion in April 2000.