The 20-year-old Pietrangelo has an unspecified upper-body injury and is questionable for Thursday's home game against Los Angeles. He leads Blues defensemen in assists (12) and points (15).
"We would anticipate it not being long-term," coach David Payne said of the injury, also confirming Tyson Strachan will take Pietrangelo's place in the lineup.
Pietrangelo left a pair of games last week but returned to finish both.
The Blues are already missing forwards David Perron (concussion), Andy McDonald (concussion) and T.J. Oshie (broken ankle) along with defenseman Roman Polak (wrist). Defenseman Barret Jackman (knee sprain) missed about three weeks earlier this season.
"Obviously, he's played very well for us and stepped up and played a lot of good minutes," forward B.J. Crombeen said. "It's obviously another loss, but it's kind of what we've been going through and something we've got to continue to work through. We've got some guys that are ready and waiting that will step in and do a great job."