Clark has been out for three weeks with an inflamed spleen. Now, the six-year veteran has been forced onto the injured reserve list.
The team also placed No. 3 tight end Jerame Tuman, who has missed the past four games with a disc problem in his back, on injured reserve. Pittsburgh had been the only franchise in the league without a single player on injured reserve before the two moves Wednesday.
Second-year veteran Anthony Smith, who started four games as a rookie and three this year, will take over Clark's free safety spot. Smith is a more physical presence in the secondary, but has less of the veteran leadership and football instincts that Clark provided.
Clark's problem with his spleen flared up after an Oct. 21 game at Denver, and the condition showed little improvement in the ensuing weeks.
Clark, 28, was signed by the Steelers as an unrestricted free agent in 2006. He was added by the club essentially as the replacement for free safety Chris Hope, who had signed with the Tennessee Titans as a free agent. Clark started 12 games in 2006 and played well, finishing the year with 75 tackles and one interception.
In 69 games with the Giants (2002-2003), Redskins (2004-2005), and Steelers, Clark has 257 tackles, four interceptions and 15 passes defensed.
Smith, a third-round choice from Syracuse in the 2006 draft, has played a lot of snaps for the Steelers and demonstrated solid productivity. He is an aggressive defender, perhaps not as accomplished in coverage as Clark, but has three career interceptions while playing largely in nickel coverage packages.
The loss of Tuman may be more significant, because coordinator Bruce Arians likes to use a lot of multiple tight end formations. Tuman, a nine-year veteran, is a good blocker and "red zone" receiver and has been more valuable than his modest statistics show.
In 120 games, Tuman has 43 catches for 509 yards and seven touchdowns.
Pittsburgh elevated two players, center Marvin Philip and cornerback Grant Mason, from its practice squad to fill the two roster spots.
Senior writer Len Pasquarelli covers the NFL for ESPN.com