Pead was helped off the field after returning a kickoff in the first quarter of a 21-7 preseason loss to the Green Bay Packers on Saturday. He didn't play in the preseason opener due to a finger injury.
''It appears that we have lost Isaiah with an ACL,'' coach Jeff Fisher said. ''After talking to our doctors, it's unlikely that he has not torn his ACL.
''We'll just hope for the best.''
It appeared Pead's knee buckled on a cut at the end of a 33-yard return. Chris Givens had a 30-yard return on the next kickoff early in the second quarter after the Packers took a 10-0 lead. Austin Franklin returned two kicks for 43 yards and Justin Veltung returned one for 29 yards.
Pead was a second-round pick in 2012 and made one start his rookie year. He appeared in 10 games last season, mostly on special teams, and had been fourth on the depth chart behind Zac Stacy, Benny Cunningham and rookie Tre Mason.
That trio combined for 60 yards on 21 carries, and rookie Trey Watts added three carries for 19 yards late in the game.
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