Culliver was injured Thursday during a non-contact drill. Defensive coordinator Vic Fangio said Friday that the loss of the third-year veteran "puts stress" on a cornerback group that faltered late last season and in the playoffs during San Francisco's run to the Super Bowl.
Culliver was San Francisco's third cornerback the past two seasons and played a key role in the team's coverage packages, often taking over at left cornerback when the 49ers went to their nickel defense.
Culliver was carted off with the knee injury barely 45 minutes into Thursday's workout. He was covering a punt in a non-contact drill when he went down in pain. He held his left knee and buried his head in his hands before being taken off the field.
Culliver had 47 tackles, two interceptions and one forced fumble last season while playing primarily as the team's third cornerback. He was drafted in the third round out of South Carolina in 2011.
"What it means right now is there are some guys getting an opportunity to show what they can do, which is a positive there. And there's people who have been doing that," coach Jim Harbaugh said Thursday.
Culliver joins a growing list of injured players for the defending NFC champions. Pro Bowl linebacker Patrick Willis suffered a "slight fracture" in an unspecified bone in his right hand during Wednesday's training camp practice, league sources told ESPN senior NFL analyst Chris Mortensen. Wide receiver Michael Crabtree suffered a torn Achilles in May and remains uncertain for the season.
Culliver made news during Super Bowl week when he responded to questions from comedian Artie Lange by saying he wouldn't welcome a gay player in the locker room. He also said the 49ers didn't have any homosexual players and, if they did, those players should leave. He later apologized.
Information from ESPN NFL Insider Adam Schefter, ESPN senior NFL analyst Chris Mortensen and The Associated Press was used in this report.