[2] He resigned from his position and left the country in 2005 in protest against certain policies of Hafez's son and successor, Bashar al-Assad.

In the course of the attack, Saif Ghobash, the United Arab Emirates' first Minister of State for Foreign Affairs was killed.

[13] As the new president, Bashar al-Assad strengthened his grip on the Baathist bureaucracy, Khaddam, and other members of the "old guard" of the government, gradually lost influence.

He announced his resignation on 6 June 2005 during the Baath Party conference after publicly criticizing the regime's many blunders, especially in Lebanon, making him the only high ranking Syrian official to publicly resign office while in Syria and at a Ba'ath Party conference, a move which many inside Syria considered extremely brave because of the potential risks involved.

[26] In an interview with Al Arabiya on the same day, Khaddam denounced Assad's many "political blunders" in dealing with Lebanon.

He especially attacked Rustum Ghazali, former head of Syrian operations in Lebanon, but defended his predecessor, Ghazi Kanaan, Syria's interior minister.

Following the Khaddam interview, the UN Commission headed by Detlev Mehlis investigating the Hariri murder said it had asked the Syrian authorities to question Bashar al-Assad and Syria's Foreign Minister Farouk al-Sharaa.

On 16 February 2008, Khaddam accused the Syrian government of assassinating a top Hezbollah fugitive, Imad Mughniyeh, "for Israel's sake.

[30] The reason for the verdict was "slandering the Syrian leadership and lying before an international tribunal regarding the killing of former Lebanese Prime Minister Rafiq Hariri.

"[30] Following his defection, Khaddam was accused of accepting German and French bribes to bury nuclear waste in the Syrian desert in the mid-1980s.

He maintained strong relations with many senior army generals who had defected from the Syrian government and was supporting them to overthrow Bashar Al-Assad.

[34] He also blamed the U.S. for "pushing Turkey into Russia’s open arms" and suggested that the U.S. had a role in the 2016 Turkish coup d'état attempt.