"We urge both the government and the demonstrators to exercise restraint at this time," he said. "The people of Uzbekistan want to see a more representative and democratic government, but that should come through peaceful means, not through violence."
That violence began in Andijon overnight, when supporters of a group of men jailed on Islamist extremism charges stormed the prison where they were being held.
Hundreds of prisoners were released, and authorities said nine protesters and police were killed in the clashes that followed.
More people were feared to have been killed later, when security forces opened fire on a square where thousands of protesters had gathered.
It's not just the violence the U.S. is expressing concern about. State Department spokesman Richard Boucher said there is another worry -- that among those freed in the jailbreak were members of an Islamist group designated terrorist by Washington.
"While we have been very consistently critical of the human rights situation in Uzbekistan, we are very concerned about the outbreak of violence in Andijon, in particular the escape of prisoners, including possibly members of the Islamic Movement of Uzbekistan, an organization we consider a terrorist organization," he said.
Uzbekistan was among the first countries to offer support to the American military in what U.S. President George W. Bush calls the "war on terror."
But Washington has continued to criticize Tashkent's human rights record in the annual report issued by the State Department.
Boucher pointed to that criticism today: "Read our human rights report, it came out two months ago. We've been very clear about the human rights situation there. We've been very factual about it, but unfortunately the facts are not pretty."
Boucher, like McClellan, expressed concern about the bloodshed and the release of prisoners, and he, too, urged both sides to show restraint:
"We think everybody should be doing everything they can to avoid violence, to calm down the situation and to deal with these differences peacefully."
He said the American embassy in Tashkent has been expressing that view to Karimov's government since the trouble began.
In Brussels, the European Union today blamed the conflict in Andijon on Karimov's government. It said it had not paid what it called "sufficient attention" to the country's problems with human rights, the rule of law, and poverty.
For more on the crisis in Uzbekistan, see RFE/RL's dedicated webpage Unrest in Uzbekistan