Under the bill, tens of thousands of undocumented Irish could apply for legal status.
The Senate fell 27 votes short of the 60 votes needed in the 100-member chamber to limit debate and advance the major overhaul towards passage.
The action follows a series of amendments that upset the delicately balanced compromise hammered out by senators and the White House.
The Senate Minority leader, Mitch McConnell, said his fellow Republicans needed more time to work on the bill that ties tough border security and workplace enforcement measures to a guest-worker program and a plan to legalise an estimated 12m illegal immigrants.
President Bush backs the compromise and lawmakers are under pressure to fix what many Americans agree is a broken immigration system through which millions of illegal immigrants have slipped into the country.
Many supporters believe this bill, which was framed by veteran Democratic Senator Ted Kennedy, is the best chance for comprehensive reform for many years.
A second vote will take place later today.
