In August 2011, Rancic and her husband announced plans to open a restaurant in partnership with Lettuce Entertain You Enterprises. The restaurant was named RPM Italian, with a menu including dishes inspired by Rancic's mother, "Mama DePandi", and it opened in the River North district of Chicago in February 2012. The partnership opened several more restaurants, including RPM Steak in Chicago, another RPM Italian in Washington, D.C., and a planned RPM On the Water opening in 2019 in Chicago. The restaurants have been popular with celebrities, including President Barack Obama and First Lady Michelle Obama.
On October 17, 2011, during an interview on Today, Rancic announced she had been diagnosed with early stage breast cancer, for which she would be treated with a double lumpectomy, followed by radiation. She underwent surgery in mid-October 2011 and returned to work at E! News about a week later. On December 5, 2011, Rancic disclosed she had decided to undergo a bilateral mastectomy.