The Lake Forest College graduate is fresh off her record-breaking swim from Cuba to Florida.
Starting Tuesday Nyad will swim 48 hours non-stop in a two-lane pool in New York City.
The event will raise funds for Americares, a nonprofit organization that delivers medicines, medical supplies and aid to people in need around the world.
"We're gonna have a rotation of a great diverse group of people for the 48 hours in the middle of the night, 2 or 3 in the morning," said Nyad. " I'm gonna have people in that pool next to me."
An estimated 25,000 east coast residents are still homeless after Hurricane Sandy.
To make a donation go to www.nyadswimforrelief.com