Betsy DeVos becomes first Trump cabinet pick to fall in danger of being voted down
The forecast became gloomy after Republican Sens. Susan Collins of Maine and Lisa Murkowski of Alaska - a pair of moderates - announced their opposition during separate Senate floor speeches.
"This is not a decision I make lightly," Collins said. "I have a great deal of respect for Mrs. DeVos. I will not, can not vote to confirm her."
After Democratic Sen. Joe Manchin of West Virginia announced his opposition to DeVos earlier Wednesday, it was expected that no Democrats would vote in favor of her nomination.
A GOP megadonor from Michigan, DeVos is a huge advocate for charter schools and voucher programs, which members of both parties expressed concerns about.
DeVos had a rocky confirmation hearing. She said guns in schools could "protect from potential grizzlies" and dodged a series of questions from lawmakers. She also faced increased scrutiny for her vast wealth - estimated in the billions - and the potential conflicts of interest that came with it.
Collins and Murkowski both voted in favor of DeVos to move her out of the Senate Committee on Health, Education, Labor, and Pensions and on to the Senate floor. That vote was a party line 12-11 result.
With Murkowski and Collins defecting for the confirmation vote, the expected tally is 50-50. That would require Vice President Mike Pence to cast a tie-breaking vote. If one additional Republican defects, DeVos' nomination would be squashed.
During Wednesday's White House press briefing, press secretary Sean Spicer expressed "100%" confidence DeVos would be confirmed.
"I have 100 percent confidence she will be the next secretary of Education," he said, later adding, "I think that the games being played with Betsy DeVos are sad."