The 37-year-old has struggled with various injuries over the last few years, most recently withdrawing from the 2025 Australian Open due to a 'very intense' foot injury.
Fognini is due to face Jacob Fearnley in his first-round match in what will be his final appearance at the prestigious tournament after 18 main-draw campaigns.
"Since I was a kid, I was coming here to say, 'Oh let's see, let's hope to play one day'," stated the Italian, whilst speaking to the Tennis Channel.
"And now I'm in the opposite [time of my career]. I think it's a good time to say goodbye in this beautiful city, special city.
"But yes, I'm here with a smile on my face because I know that I had a really difficult time during my 15, I don't know, 16, 20 years in Rome and I would like to enjoy the last lap."
Fognini famously defeated the then-world No. 1 Andy Murray 6-2, 6-4 in a raucous second-round match in 2017, and it is this meeting that the Italian picked as his best Rome memory.
"One is for sure the victory in the night against Andy Murray when he was No. 1 in the world," answered Fognini.
"This one is in the special place, especially here in Rome, for sure. I'd say it's top three in my career.
"I live for [those] moments. My character is like that. I play with passion, and sometimes too much. But I think when I was playing my best tennis here, I think the crowd was really happy to see me beating Andy. I beat Gael, I beat Tsonga, I beat a lot of good players.
"Of course, the dream since I was a kid was winning here. But if I have to be honest, I have now and have in the future also the opportunity to say to Federico and the two girls that I was able to play against Roger, against Rafa, against Andy, against Novak, and this part of my career was really special."
The former ATP world No. 9's best result at the Rome Masters was a quarterfinal showing in 2018, where he lost to eventual champion Rafael Nadal.
In 2024, during his latest campaign, Fognini lost to Taylor Fritz.