The Bronzeville neighborhood campus, located near 35th Street and South Michigan Avenue, is now coed.
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"It's nice to know you're making history for De La Salle. I'm lucky to be a part of it," said junior Caroline Wood.
The legendary all-boys Catholic high school will now have girls and boys sitting side-by-side in class. Five former Chicago mayors, including both Mayor Daleys, attended the school.
"Energy level is really high. Intense for everyone; we don't know what's going to happen," said senior Brycen Pitre.
Previously, the school was co-institutional, which means that girls studied at another site located a mile and a half away in the Bridgeport neighborhood.
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Father Paul Novak, the school president, said the decision to combine campuses came after talking to parents.
"After polling our potential parents and current parents, they were telling us they preferred De La Salle to have a co-education environment," Novak said.
Novak projects enrollment will increase from 920 to more than 1,000.
At a Monday morning school-wide assembly, the students were told to play hard, study harder and shine during the school year.