Macchiarini performed two synthetic trachea transplants on Yesim Cetir, 26, in Stockholm in 2012 and 2013, but she suffered brutal complications until her death.
In the early hours of Monday, her father Hayrullah Cetir announced on his Facebook account that Yesim died at Temple University Hospital in Philadelphia.
"My daughter Yesim died tonight [Sunday] at 9.15pm may she rest in peace," he wrote, publishing a picture of her in a hospital bed.
Macchiarini operated on eight patients between 2011 and 2014, three of them at the prestigious Stockholm-based Karolinska Institute, which selects the winners of the Nobel Prize in medicine.
Only one of the patients survived after having a synthetic trachea, designed and implanted by Macchiarini, removed during a surgery in Russia in 2014.
Cetir was the victim of two failed surgeries as her trachea was first badly damaged during treatment in Turkey before she received surgery in Stockholm.
She went to the United States to receive a trachea from a donor, without being able to recover.
"It is with great sorrow that I offer my sincere condolences to Yesim Cetir's family after having heard about her death. It would of course be inappropriate to discuss her earlier medical condition and treatment," Macchiarini said in a written comment to Swedish public broadcaster SVT.
The surgeon gained worldwide fame in 2011 by carrying out the world's first graft of an artificial plastic trachea, which was to be colonized by the patients' stem cells.
While he said in the medical journal The Lancet that the technique was working, successive deaths of his patients and falsifications in the article led him to be sacked.
Macchiarini was suspected of having embellished his resume to be hired by the Karolinska Institute. He is being investigated by Swedish police.
The scandal hit the Nobel Prize and caused several resignations within the institute.