Explosions at the al-Askari shrine in Samarra, north of the Iraqi capital Baghdad, have destroyed both its minarets.
Witnesses say the mosque, one of Shia Islam's holiest sites, was hit by two bombs at around 0900 (0500 GMT).
The two minarets used to stand either side of the mosque, which houses the remains of two revered Shia imams.
Police reinforcements were rushed to Samarra after the attack, which prompted demonstrations by angry Shias.
The minarets survived an earlier attack in February 2006, which destroyed the mosque's famous golden dome and led to a wave of sectarian violence.
The site is of immense spiritual importance for Shia Muslims around the world and has attracted millions of pilgrims over the centuries, such as these in 2004.