The cat's owner, Marty Stevens, said veterinarians believe the cause of death was cancer.
Frank and Louie made it into the 2012 edition of Guinness World Records as the longest-surviving member of a group known as Janus cats, named for a Roman god with two faces.
Janus cats almost never survive, and most have congenital defects.
They usually only live a few days.
A breeder brought the rare feline to Stevens, a vet nurse, to be euthanized in September of 1999.
However Stevens, not believing the cat would survive, decided to take him home with her and care for him.
She fed Frankenlouie using tubes in both mouths, soon realizing that only the 'Frank' side was connected to his esophagus.
He did, however, eat enough for two.
Stevens said her cat quickly developed a strong personality and loved to walk around her neighborhood in North Grafton.
'He's just so affectionate and sweet he usually wins people over,' she told The Telegram-Gazette in 2011.
He functioned as a regular cat.
While blind in his center eye, both his outer eyes worked fine, and while he had two noses and mouths, he had only one brain.
Stevens is now understandably devastated to lose her pet of 15 years.
She said her fell quite ill around Thanksgiving and she she took him to the Tuffs University clinic.
The vet told her it was best to euthanize him, because he was in quite a lot of pain.
Stevens says once her sadness passes she wouldn't mind looking for another Janus to bring home with her, just like she did with Frankenlouie in 1999.
'I would love to do it again,' she said.
- Daily Mail