Police said the crash happened in the Hegewisch neighborhood's 2700-block of East 130th Street around 9:15 a.m.
A semi was heading eastbound on 130th Street and tried to make a left turn, police said. That's when a Dodge Grand Caravan, which was also traveling eastbound, rear-ended the semi.
Two males of unknown ages were inside the Dodge. They were transported to the University of Chicago Medical Center, where both were pronounced dead, police said. Their names were not immediately released.
No other injuries were reported. CPD's Major Accidents Investigation Unit is investigating.
Authorities did not immediately provide further information about the crash.