Florida Sens. Marco Rubio and Bill Nelson were on opposite sides of a bipartisan immigration bill that died Thursday afternoon amid a veto threat from the White House.
Rubio, who helped write the 2013 bipartisan immigration overhaul, voted against the bill, while earlier indicated he could be supportive. Nelson voted for the measure.
It would have provided 1.8 million Dreamers a chance for citizenship plus budgeted $25 billion for a border wall.
The bill was crafted by moderate Republicans and Democrats billing themselves as the "Common Sense Coalition." They described the proposal as having the most bipartisan support in the Senate, but it came under fire from the White House and the Department of Homeland Security.
The vote was 54-45, six votes short of the 60 needed to advance.
The moderates' measure does not alter a lottery that distributes about 55,000 visas annually to people from diverse countries. Trump has proposed ending it and redistributing its visas to other immigrants.
The group spent weeks trying to craft a middle ground on the thorny immigration issue.
The defeat casts serious doubt about a solution for the Dreamer issue.