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Sophia Grisanti was born in Sicily to Angelo and Eleanor Grisanti. She had a sister Angela, a sister Regina and a brother Angelo. Although another brother was mentioned, he was unnamed and only spoken of a few times. Dorothy mentions an "Uncle Vito" in Season 2 but it is unclear whether he is Sophia's brother or the brother of her husband, Salvadore. In the first episode of The Golden Palace (1992) Sophia's age was said to be 87 years old but in her many flashbacks to life in Sicily, she frequently places herself as being a young woman (having romantic affairs) in dates between 1912 and 1920.

As a teenager in Sicily she was briefly engaged to a young man from her village named Augustine Bagatelli and also claims that she was once engaged to her brother - something largely dismissed as a joke in the episode. Later, she became engaged to Giuseppe Mangiacavallo, who jilted her at the altar. Sophia's first marriage to Guido Spirelli (she was 14 and it was an arranged marriage) ended in annulment, after which, she moved to New York. Sophia later married Salvadore "Sal" Petrillo and had three children with him: Dorothy, Phil and Gloria.

In her later years, Sophia suffered a stroke - the effects of which are said to be a partial explanation for Sophia's blunt, uncensored, and brazen remarks. She was subsequently placed in Shady Pines Retirement Home by her daughter, Dorothy. However, after Shady Pines was damaged in a fire, Sophia moved in with Dorothy.

Due to Sophia's Sicilian descent, there were regular hints in the series that she and her family have some mafia connections. She made reference to several vendettas and it is even hinted that Sophia herself has done mob work; she once stated that no one in her family had "ever left a body to be found". Sophia also claimed to have been present at the 1929 St. Valentines Day Massacre, to which she then took back stating, "Oh yeah, I was at the movies that day. All day."

In the series finale of The Golden Girls, Sophia, after initially deciding to follow the now-married Dorothy out of the house, turns back and decides to stay with Rose and Blanche, which sets up the transition to The Golden Palace. After the events of The Golden Palace (which ended without a series finale), Sophia returns to the Shady Pines nursing home, joining the cast of Empty Nest.

Sophia is best known for her wisecracks, put-downs and brazen remarks, often commenting on Dorothy's unmarried state, Blanche's promiscuity, and Rose's cluelessness. However, despite her sharp criticism of her daughter and roommates, she loves and cares for them deeply; she even sees Rose and Blanche as surrogate daughters. The other women usually seek Sophia out for advice, which she is all too willing to share, usually beginning with her catchphrase, "Picture it…".

Outside The Golden Girls, Sophia appears on two episodes of Empty Nest ("Libby's Gift" and "Windy") before becoming a regular for the final two seasons. She also appears on the Blossom episode "I Ain't Got No Buddy" and the Nurses episode "Temporary Setbacks".