The Lebanese government has approved a UN draft setting up an international tribunal to try suspects in the assassination of Rafiq al-Hariri.
Al-Hariri, a former Lebanese prime minister, was killed in February last year in a bomb blast in Beirut.
"Our aim is to achieve justice and only justice. Without it - and without knowing the truth - the Lebanese will not rest and we cannot protect our democratic system and political freedom," Siniora said on Monday.
"We tell the criminals that we will not give up our rights, no matter what the difficulties and obstacles are," he said.
The resignations left the 18 remaining ministers approving the United Nations document, and they defended the cabinet's decision as legal.
Ghazi Aridi, the information minister, quoted Siniora as saying: "It is 100 per cent constitutional."
Syrian involvement
A UN investigation has implicated senior Syrian officials, but Syria has denied any role in the assassination.
Al-Hariri was killed along with 22 others in a truck bombing.
The assassination caused large anti-Syrian protests in Beirut, the Lebanese capital, and led to the withdrawal of Syrian troops from Lebanon, ending a 29-year military presence.
Subsequent elections brought an anti-Syrian majority to power in parliament and the cabinet.