"We have killed over 60,000," Gen. Raymond "Tony" Thomas, commander of US Special Operations command, told a symposium Maryland.
Thomas oversees America's elite Special Operations troops, including Navy SEALs and Army Green Berets, which have played a large role in combating the terror organization, including raids against key leaders.
His estimate represents a sharp increase over recent numbers provided by the US and its allies.
A senior US military official told CNN in December that as many as 50,000 ISIS fighters had been killed, calling that figure a conservative estimate.
The US-led coalition has ramped up airstrikes against the terror group's self-declared capital in Raqqa, Syria, in recent weeks, while Iraqi troops, backed by US air power, have continued their assault on Mosul. They have so far succeeded in driving ISIS from the eastern part of Iraq's second-largest city.
This uptick in fighting could be one reason for the new body count estimate, as coalition leaders have said that thousands of ISIS fighters have been killed in the battle for Mosul.
But later in December, UK Defense Secretary Michael Fallon provided reporters in London with a much smaller number, around 25,000 fighters for ISIS, also known as Daesh.
"More than 25,000 Daesh fighters have now been killed," Fallon said while appearing alongside his then-American counterpart, Ash Carter.
The sharp difference in the UK and US estimates underscores the challenge of assessing enemy casualties, even among close allies that share intelligence, and could complicate the current White House-directed effort to develop a plan to defeat ISIS.
Multiple American officials have told CNN in the past that the Pentagon does not officially tally body counts.
Carter's predecessor, Chuck Hagel, said that the practice of counting the number of enemies killed wasn't a particularly useful one.
"My policy has always been, don't release that kind of thing," Hagel told CNN's Wolf Blitzer in December.
Hagel, a veteran of the Vietnam War where the American military's enemy body count statistics were disparaged for being overly optimistic, criticized releasing the figures.
"Body counts. I mean, come on, did we learn anything from Vietnam?" he asked. "Body counts make no sense."
"References to enemy killed are estimates, not precise figures," said Christopher Sherwood, a Department of Defense spokesman. "While the number of enemy killed is one measure of military success, the coalition does not use this as a measure of effectiveness in the campaign to defeat ISIS."