Heavy equipment was brought in to clear debris so firefighters could reach the building, still burning hours later. Police say they believe the blast was a suicide bombing.
In pictures: Islamabad blast; The explosion is thought to have been caused by more than a tonne of explosives and police are warning that the hotel could collapse. The BBC's defence and security correspondent, Rob Watson, says that the attack bears the hallmarks of al-Qaeda, given the scale, target and what would appear to be the careful political timing involved.
He says the attack is without doubt the most serious in the Pakistani capital to date and will spark fears about the country's stability in the face of a growing Islamist insurgency. A huge area of the 290-room hotel remained on fire hours after the explosion. The BBC's Barbara Plett, at the scene, said the emergency services had been unable to reach the upper floors of the hotel, where more people were feared to be trapped.
At least 100 people have been injured in the attack, among them four British citizens as well as Saudi, German, Moroccan and Afghan nationals. A hotel employee, Mohammad Sultan, said he was in the reception when something exploded, forcing him to the ground. "I don't understand what it was, but it was like the world is finished," he told the Associated Press news agency.
There are reports that at least 200 people were in the hotel's restaurants at the time of the explosion, many breaking their Ramadan fast. The Marriott is the most prestigious hotel in the capital, and is popular with foreigners and the Pakistani elite. The hotel is located near government buildings and diplomatic missions, so security is tight, with guests and vehicles subject to checks.
The Marriott has previously been the target of militants. Last year a suicide bomber killed himself and one other in an attack at the hotel. Insurgency
In an interview with the BBC, Senator Enver Beg, from the Pakistan People's Party, appealed to the international community for help in the struggle against terrorism.
"Pakistan is a frontline country in the war on terror. We are, again, with suicide bombings which are taking place all over the country. "Our economy is affected because of these terrorist activities. And I think the international community has to come out and help Pakistan to fight against this terrorism," he said.
Pakistan has been a key ally of the US in its "war on terror"The White House condemned the attack and said it was "a reminder of the threat we all face".
The US would "stand with Pakistan's democratically elected government as they confront this challenge", the statement added.
Pakistan has been a key ally of the US in its "war on terror", but relations have become strained over tactics. In recent months Pakistan has voiced growing disquiet over US raids targeting militants in its territory, launched from neighbouring Afghanistan. Al-Qaeda and Taleban militants based in Pakistan's north-west tribal region have repeatedly carried out attacks across the border in Afghanistan.