The ruling clears the way for the government to remove its endorsement from Avastin.
When it was first introduced, Avastin was considered a wonder drug, and many breast cancer patients believe it's keeping them alive.
The unprecedented vote Wednesday by the Food and Drug Administration advisory panel comes less than a year after the same panel reached the same conclusion.
In three unanimous votes, the six members of the FDA oncology drug panel voted that Avastin is ineffective, unsafe and should have its approval for breast cancer withdrawn.
"I think we all wanted Avastin to succeed but the reality is that these studies did not bear out that hope," said Natalie Compagni-Portis, the lone patient representative on the FDA panel.
The vote is not binding and FDA Commissioner Margaret Hamburg will make the final decision.
Immediately after the final vote, patients in the audience erupted in shouts against the FDA and its panelists.
"What do you want us to take!? We have nothing else!" shouted Christi Turnage, of Madison, Miss. Turnage said her cancer has been undetectable for more than two years since starting therapy with Avastin.
The drug was approved in 2008 to treat advanced-stage breast cancer that has spread to other parts of the body. But the concern is over the drug's effectiveness and its side effects, like holes in the stomach and intestines, severe bleeding and blood clots.
Nearly 100,000 women have used Avastin. If the FDA pulls the plug on Avastin, doctors could still prescribe it, but insurance companies wouldn't cover it. One year's treatment can run more than a $100,000.
Assuming the FDA follows through on the withdrawal, drugmaker Roche could lose up to $1 billion in revenue for its best-selling product, which generates over $6 billion per year.
The Associated Press contributed to this story.