Speaking to reporters traveling with him to Brussels, Mattis noted there has been no such attack since the White House issued a surprise statement Monday night that threatened President Bashar Assad's government with "a heavy price" if it used chemical weapons.
The US says it saw active preparations at Syria's Shayrat airfield for using such weapons.
Mattis wouldn't say what specifically triggered US concerns that an attack might be imminent. He said President Donald Trump has showed "how seriously we took them."
Syria and its allies, Russia and Iran, have rejected the US allegation and say Assad's forces never previously used chemical weapons. The US so far hasn't provided details to bolster this week's claim of a chemical attack being planned.
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The UN has ascribed responsibility to Assad's government for three previous attacks during Syria's six-year civil war.
In April, Trump ordered almost 60 cruise missiles to be fired at the Shayrat base after accusing Syria of killing dozens of civilians in a sarin gas attack.
Asked if any chemical weapons activity beyond Shayrat has been seen, Mattis told reporters traveling with him to Brussels: "I think that Assad's chemical program goes far beyond one airfield.