The bomber struck during the main weekly prayers in Eastern Province yesterday, where assailants linked to the Sunni extremist IS killed seven members of the minority Shiite community in November.
The interior ministry said a suicide bomber detonated a bomb at the mosque in Kudeih, in the Shiite-majority city of Qatif, the official SPA news agency reported.
"An individual detonated a bomb he was wearing under his clothes during Friday prayers at Ali Ibn Abi Taleb mosque in Kudeih in Qatif," the ministry spokesman said in a statement.
IS said it was behind the attack, the first time the group has officially claimed an attack in Saudi Arabia, and vowed "dark days ahead" for Shiites until militants "chase them from the Arabian Peninsula".
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IS considers Shiites as heretics.
A statement published online said "soldiers of the Caliphate" were behind the attack by Abu Amer al-Najdi who "detonated an explosives belt" in the mosque.
The United States condemned the bombing, but White House spokesman Josh Earnest said it was not immediately able to confirm it was the work of IS.
News websites in eastern Saudi Arabia posted photographs of bodies lying in pools of blood, bloodied prayer rugs and damage inside the mosque.
Qatif hospital issued an urgent call for blood donations and called in off-duty staff to cope with the high number of casualties, an activist said.
Qatif resident Naseema Assada said worshippers were celebrating the birth of revered Shiite Imam Hussein when the blast occurred.
"The people are very angry," she said, adding that they tried to stop police from entering Kudeih.