On Wednesday, the US Treasury Department placed Assef Shawkat on a list of "specially designated nationals" under a presidential anti-terrorism order, freezing any US assets he holds and barring US citizens from transactions with him.
Stuart Levey, the Treasury's undersecretary for terrorism and financial intelligence, said the director of the powerful Syrian Military Intelligence (SMI) agency had been "a key architect of Syria's domination of Lebanon".
In a statement, Levey said, Shawkat was also "a fundamental contributor to Syria's long-standing policy to foment terrorism against Israel".
In addition, Shawkat "has access to the highest levels of the Syrian power structure" by virtue of his marriage to Bushra al-Assad, Bashar al-Assad's sister".
Shawkat is a close confidant of al-Assad and an important member of his inner circle of advisers, the Treasury said.
Rustum Ghazali was blacklisted
by the US Treasury in June 2005
The action comes after the Treasury in June blacklisted Ghazi Kanaan, Syria's deceased interior minister, and Rustum Ghazali, its former spymaster for Lebanon, under the same anti-terrorism order.
The Syrian government condemned that action, calling it a deliberate ploy to "divert attention from Israeli aggressions" in southern Lebanon.
The Treasury said Shawkat had been a major player in Lebanon through his oversight of SMI activities in the neighbouring country and his "direct control" over Ghazali.
A UN investigation has implicated Syrian intelligence in the assassination of former Lebanese premier Rafiq al-Hariri in February last year. Shawkat was among the officials named as suspects in a UN report.
Al-Hariri's murder in a Beirut car-bombing triggered a massive outcry in Lebanon, led to the withdrawal of Syrian troops from the country and increased international pressure on al-Assad's regime.
The US Treasury said that as the SMI chief, Shawkat had co-ordinated with several extremist groups including Hizb Allah, Hamas, the Popular Front for the Liberation of Palestine and Palestinian Islamic Jihad.