She also won the road race at the London Olympics and has world and Olympic titles in cyclo-cross and track cycling.
So who can challenge her?
"The whole Italian squad is very strong," she said. "They have several cards to play. Then there are some individuals, and the Americans."
Italians have won the race four times in the last six years. Maria Bastianelli won it in 2007, Tatiana Guderzo in '09 and Giorgia Bronzini in '10 and '11.
Another contender is Emma Johansson of Sweden, who finished second to Vos in this year's World Cup.
Among the U.S. riders, there's Carmen Small and Evelyn Stevens, who finished third and fourth, respectively, in the individual time trial on Tuesday, and Mara Abbott, who won this year's women's Giro d'Italia.
"With the climbs," Vos said, "for sure (Abbott) is one of the favorites."