49ers star inside linebacker Patrick Willis suffered a slight fracture in his right hand during Wednesday's practice and is unlikely to participate in any preseason games.
Willis has played with a cast on his hand in three separate instances in 2007, 2010 and in college at Ole Miss in 2005.
ESPN's Chris Mortensen first reported news of the slight fracture on Twitter.
Jim Harbaugh is scheduled to meet with the media at 4 p.m. Thursday.
The news comes nearly two months after San Francisco lost leading receiver Michael Crabtree with a torn Achilles that will keep him out until at least November. Fellow receivers Kyle Williams, A.J. Jenkins and Kassim Osgood are also dealing with injuries that have forced them out of multiple practices this week.
NaVorro Bowman and Aldon Smith have both missed practices this week while dealing with injuries. Bowman reportedly suffered a groin strain Sunday, missed Tueday's session and returned to practice in a limited capacity Wednesday. The team has not commented on Smith's status after he missed Wednesday's practice.
The 49ers begin their defense of NFC Championship Sept. 8 when they host the Green Bay Packers. That gives Willis 38 days to recover before the start of the regular season.
Willis has 1,029 tackles in 92 games since San Francisco drafted him in the first round of 2007. He has been named an All-Pro in each year of his career and finished second on the team in tackles in 2012 with 171. He finished behind Bowman, who made 183.
The team has offered no timetable on Willis' return as of yet. He injured his hand during a one-on-one blitz pickup drill against fullback Bruce Miller.