The talks at Chequers, Cameron's country retreat, with Pakistan President Asif Ali Zardari and Afghan President Hamid Karzai will focus on cross-border security and the prevention of a "Taliban resurgence" when foreign troops leave Afghanistan by the end of next year.
They are also expected to concentrate on how Pakistan and the international community can support the Afghan-led peace process.
The in-depth talks today follow a private dinner hosted by Cameron for Zardari and Karzai last evening at Chequers, north of London in Buckinghamshire.
Before start of the trilateral summit, the three leaders also had breakfast and then they stood together for photos at the countryside residence of the British Prime Minister.
Prime Minister's spokesperson confirmed that foreign ministers, chiefs of army staff, chiefs of intelligence and the chair of the Afghan High Peace Council are also involved in the talks for the first time and that the leaders are expected to make a joint statement later today.
"This trilateral process sends a very clear message to the Taliban: now is the time for everyone to participate in a peaceful political process in Afghanistan. As the prime minister has set out previously, a stable Afghanistan is not just in the interests of Afghans, but also in the interests of their neighbours and the UK," the spokesperson said.
"We share the same vision for Afghanistan: a secure, stable and democratic country that never again becomes a haven for international terror," he added.
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This is the third round of discussions since Cameron initiated the three-way process last year, when the three leaders met in Kabul and New York.
With the NATO withdrawal expected in 2014, Karzai has said that he does not want a repeat of the mistakes made when Russia withdrew from Afghanistan a quarter of a century ago, plunging the country into civil war.
Karzai, however, questioned the real motive behind troop withdrawal by the West, which includes around 9,000 British troops.
"They feel fulfilled with regard to the objective of fighting terrorism and weakening al-Qaeda, or they feel that they were fighting in the wrong place in the first place, so they should discontinue doing that and leave," Karzai said.
"There will not be peace in Afghanistan by having an agreement only between us and the Afghan Taliban. Peace will only come when the external elements involved in creating instability and fighting, or lawlessness in Afghanistan, are involved in talks," he was quoted by the Guardian as saying.