Karshi-Khanabad air base in south-eastern Uzbekistan, which the US has been given six months to leave, has played a key role in supporting US operations in Afghanistan since 2001.
The loss of the base will also hit the local Uzbek economy
Its location in a secure area, a short journey from the border with Afghanistan, makes it an ideal logistical centre outside the field of military operations.
Known by US troops as K2, it is used as a landing base for humanitarian goods, which are then taken by road into often inaccessible areas of northern Afghanistan.
Its long runway also makes it useful for refuelling large military aircraft.
Uzbekistan's authoritarian President, Islam Karimov, initially courted Washington as a counter-balance to the traditional regional power, Russia.
But relations have plummeted since the Andijan killings in May, when Uzbek troops fired into crowds of demonstrators to crush an anti-government protest.
The Uzbek authorities restricted flights into Karshi-Khanabad after the US backed calls for an independent inquiry into the incident, described as a "massacre" by aid agency Human Rights Watch.
The eviction notice from the Uzbek government came days before a senior US official was to travel to Tashkent for talks about Andijan, human rights and political reform, according to The New York Times.
"To say that the US leadership and the Uzbek leadership don't see eye-to-eye with one another today is an understatement," Martha Brill Olcott, a Central Asian expert with the Carnegie Endowment for International Peace, told the US press.
The US has one other base in the region, in neighbouring Kyrgyzstan, but it has no road access to Afghanistan.
During a trip to Kyrgyzstan earlier this week, Defence Secretary Donald Rumsfeld shrugged off suggestions that US operations would be hurt if the Uzbek government denied them use of K2.
"We're always thinking ahead," he said. "We'll be fine."
Fiona Hill, a Russia expert with the Brookings institute in Washington, told the BBC that the US military would have prepared for this.
"Even before the events in Andijan, there was a great deal of discussion... about the fact that Uzbekistan was increasingly a strategic liability rather than an asset," she said.
However, the base's closure - and the loss of the jobs and money it brings to the area - would be another blow to the struggling Uzbek economy, a major source of simmering discontent in an increasingly unstable country, says the BBC's Ian MacWilliam.