There was no suggestion of any racial motive on the part of the gunman who shot dead 19 children and two adults at an elementary school in Uvalde, Texas.
But the shock of the bloodshed, less than two weeks after the May 14 murders in Buffalo, New York, has catapulted America's gun violence crisis back to the top of the agenda in Washington.
"The bill is so important, because the mass shooting in Buffalo was an act of domestic terrorism. We need to call it what it is: domestic terrorism," Democratic Senate leader Chuck Schumer said ahead of the vote.
The Domestic Terrorism Prevention Act would have created units inside the FBI and Departments of Justice and Homeland Security to combat domestic terror threats, with a focus on white supremacy.
A task force that includes Pentagon officials would also have been launched "to combat white supremacist infiltration of the uniformed services and federal law enforcement."
Schumer had urged Republicans Wednesday to allow the chamber to start debate on the bill, offering to accommodate Republican provisions to "harden" schools in the wake of the Texas murders.
Just ahead of the vote, Schumer said he had wept while studying pictures of the young victims, calling the state's pro-gun governor, Greg Abbott, "an absolute fraud."
Abbott has made efforts to loosen gun restrictions in Texas, including signing into law a measure last year authorizing residents to carry handguns without licenses or training.
The domestic terrorism bill's 207 co-sponsors included three moderate Republicans in the House.
But there was not enough support in the evenly split 100-member Senate to overcome the Republican filibuster -- the 60-vote threshold required to allow debate to go forward.
Republicans say there are already laws on the books targeting white supremacists and other domestic terrorists, and have accused Democrats of politicizing the Buffalo massacre, in which 10 Black people died.
They have also argued that the legislation could be abused to go after political opponents of the party in power.
Democrats are looking for Republicans to support a separate gun control bill, and said Wednesday they would work over the coming days to see if they could find common ground with enough opposition senators to circumvent a filibuster.
"Make no mistake about it, if these negotiations do not bear fruit in a short period of time, the Senate will vote on gun safety legislation," Schumer said
