He said the US also would push for broader political changes in the Middle East country.
Speaking at Stanford University yesterday after being introduced by former top diplomat Condoleezza Rice, Tillerson said the Trump administration was determined not to repeat President Barack Obama's "mistake" when he withdrew US troops from Iraq in 2011.
Republicans for years have argued the withdrawal created the opening for IS' rapid expansion.
Instead, Tillerson stressed that US forces would remain in Syria for the foreseeable future as President Donald Trump and his aides implement a new strategy to stabilize Syria, where a civil war has killed as many as a half-million people and created millions of refugees since 2011.
"Let us be clear, the United States will maintain a military presence in Syria focused on ensuring ISIS cannot re-emerge," Tillerson said.
Recounting what he said went wrong in Iraq, Tillerson said: "We cannot allow history to repeat itself in Syria. ISIS presently has one foot in the grave and by maintaining an American military presence in Syria until the full and complete defeat of ISIS is achieved, it will soon have two."
Beyond counterterrorism, though, Tillerson outlined a much broader mission for US forces in Syria than when Trump first entered office with an almost singular focus on defeating terrorists.
Backed by Russia and Iran, Assad has reasserted control over much of Syria. And Republicans and Democrats in the US have grown worried that both of Assad's allies are now entrenched in the country, with Iran in particular posing an immediate threat to neighboring Israel.
Military leaders, meanwhile, worry that Assad's inability to quell local unrest will mean that IS or another such formation is likely to reappear in the future.
Washington won't allow international reconstruction aid to flow to any part of Syria under Assad's control, he said. It will discourage countries from trading with his government.
"Instead, we will encourage international assistance to rebuild areas the global coalition and its local partners have liberated," Tillerson said, suggesting such an approach might pressure Assad to resign.
"Once Assad is gone from power, the United States will gladly encourage the normalization of economic relationships between Syria and other nations."
More immediate, Tillerson called for Russia to continue working with the US on a "de-escalation" area in southwest Syria and stick to commitments to a U.N.-led peace process.
In Syria, the United States also is contending with disagreements with close partner Turkey. The NATO ally is fiercely opposed to an expanded training program for Kurdish and Arab border guards in Syria. It sees the Kurdish forces working with the United States as an extension of the Kurdish insurgency in Turkey.
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