The new charges against 22-year-old Jared Loughner include the shooting death of U.S. District Judge John Roll and Rep. Gabrielle Giffords' aide Gabe Zimmerman. The federal charges are separate from state charges in the incident.
U.S. Attorney Dennis Burke called the 49-count indictment against Loughner "comprehensive and is solid, and covers all the murdered and injured victims" who were at the political event held by Giffords outside a Tucson grocery store.
The mass shooting left 13 people wounded and six people dead.
Loughner had pleaded not guilty to earlier federal charges of trying to assassinate Giffords and kill two of her aides.
Loughner is scheduled for a court hearing next Wednesday.
Federal prosecutors haven't yet said whether they will seek the death penalty, but legal experts believe it's a virtual certainty.
The Associated Press contributed to this story.