The White House believes more than 20,000 Russian combatants have died in the battle for the Ukrainian city of Bakhmut in the last five months.
A further 80,000 have been wounded, National Security Council spokesman John Kirby said, citing newly declassified intelligence.
Half of the dead are from the Wagner private mercenary company, the US says.
If accurate, the number of Russian casualties outweighs the eastern city's pre-war population of about 70,000.
Moscow has been trying to take Bakhmut since last year in a grinding war of attrition.
The battle for the small city - where only a few thousand civilians remain - has taken on huge symbolic importance for both sides.
Ukrainian officials have also said they are using the battle to kill as many Russian troops as possible and wear down its reserves. However, Ukraine only now controls a small portion of the city.
"Russia's attempt at an offensive in the Donbas largely through Bakhmut has failed," Kirby told reporters. "Russia has been unable to seize any real strategic and significant territory."
"We estimate that Russia has suffered more than 100,000 casualties, including over 20,000 killed in action," he added.
The toll in Bakhmut accounts for losses since the start of December, according to the US figures.
"The bottom line is that Russia's attempted offensive has backfired after months of fighting and extraordinary losses," Kirby said.
He added he was not giving estimates of Ukrainian casualties because "they are the victims here. Russia is the aggressor".
The BBC is unable to independently verify the figures given and Moscow has not commented.
The capture of the city would bring Russia slightly closer to its goal of controlling the whole of Donetsk region, one of four regions in eastern and southern Ukraine annexed by Russia last September following referendums widely condemned outside Russia as a sham.
Analysts say Bakhmut has little strategic value, but has become a focal point for Russian commanders who have struggled to deliver any positive news to the Kremlin.
'We need to stop lying to the Russian population'
The Wagner mercenary group - which has become notorious for its often inhumane methods - has taken centre stage in the Russian assault on Bakhmut.
Its leader, Yevgeny Prigozhin, has staked his reputation, and that of his private army, on seizing the city.
But he recently threatened to pull his troops out of Bakhmut.
In a rare in-depth interview to a prominent Russian war blogger, he vowed to withdraw Wagner fighters if they are not provided with much-needed ammunition by the Russian defence ministry.
Wagner fighters could be redeployed to Mali, he warned.
He has often clashed with Russia's defence ministry during the war, accusing officials of not providing his fighters with enough support.
Prigozhin also called upon the Russian media and military leadership to "stop lying to the Russian population" ahead of an expected Ukrainian spring counteroffensive.
"We need to stop lying to the Russian population, telling them everything is alright," he said.
He praised the Ukrainian military's "good, correct military operations" and command.
A top Ukrainian general said on Monday that counterattacks have ousted Russian forces from some positions in Bakhmut but the situation remained "difficult".
New Russian units, including paratroopers and fighters from Wagner, are being "constantly thrown into battle" despite taking heavy losses, General Oleksandr Syrskyi, the commander of Ukraine's ground forces, said on Telegram.
"But the enemy is unable to take control of the city," he said.