Colts offensive lineman Ben Ijalana and linebacker A.J. Edds have both suffered season-ending torn anterior cruciate knee ligaments.
It's the latest setback for Ijalana, a second-round pick last year who tore the same left ACL in his fourth game as a rookie.
"You hate to lose anybody in camp or at any time during the season, especially Ben," coach Chuck Pagano said. "The guy came back, had a significant knee injury, same knee, two hip surgeries, busted his rear to get healthy and get back and then unfortunately something like this happens.
"A.J., the same thing, all the hard work and time and preparation these guys have put in and then to come out here and in basically a non-contact drill and it happens.
"We feel bad for those guys. They'll be back. They'll rehab just as hard as they did before, but we look for the next man to step up."
The team was looking to bring in players for tryouts this week to fill the two roster spots.
Meanwhile, Pagano was pleased with the Colts' first practice in pads before taking a day off Thursday.
"(The players) came back in great shape," Pagano said. "This is not an easy practice. We're out here for quite some time, and anytime you slap the pads back on like I said you're running around in shorts it's easy there's an acclamation period that we got to go through. There is an acclamation period getting used to the pads. So I thought they handled today pretty well."