Murray and Fognini have competed against each other since they were aged 11 and first played on the ATP Tour in 2007Andy Murray's recent revival on clay was halted by defeat in an eventful Italian Open first-round match against home favourite Fabio Fognini.
The 35-year-old Briton, who won a Challenger title in France last week, lost 6-4 4-6 6-4 in Rome.
Fognini, 35, showed his classy ball-striking to win the first set, before Murray eventually clinched a second set that had seven breaks of serve.
But the Italian rediscovered his level, serving clinically, to win the decider.
Murray was playing on the Rome clay for the first time since 2017, when he was the defending champion and ranked as the world number one.
Since coming back from hip surgery in 2019, which he thought would end his career, Murray has protected his body with limited appearances on the clay.
This year, he is targeting a return to the French Open and making only his second appearance at the clay-court Grand Slam event since 2017.
After starting this season's European swing with one-sided defeats in Monte Carlo and Madrid, the 2016 Roland Garros finalist decided to gain more match practice by playing in the Aix-en-Provence event on the second tier of the ATP Tour.
The move paid dividends as he beat a strong field to win the trophy and earn valuable playing time.
However, his defeat by Fognini means he is unable to string together more matches in what is scheduled to be the Scot's final tournament before playing in Paris.
Back up to 42 in the rankings, Murray's serve came under severe pressure as he fell behind early on.
Fognini, a former top-10 player now ranked 130th, demonstrated his class with confident returning off both flanks and several stunning winners.
The unpredictable Italian also showed a grittier side to hold off three break points for a 4-2 lead and, after serving out the opening set, Fognini saved six more break points at the start of the second.
But his concentration suddenly dropped as back-to-back double faults handed over the break for Murray, who turned a 2-0 lead into a 5-1 advantage.
Fognini put the set back on serve, helped by Murray's first double fault of the match at 5-3, only for Murray to break serve again and send the match into a decider.
One of the best ball-strikers and movers on clay, Fognini rediscovered his intensity - as Murray faded - to win an entertaining match lasting almost three hours.
What else happened in Rome?
Former British number one Kyle Edmund lost 6-1 6-3 in the first round to France's Alexandre Muller.
Edmund, 28, played under a protected ranking as he continues his comeback from three knee operations.
However, he was not able to beat 100th-ranked Muller and set up a second-round meeting with British number one Cameron Norrie.
Edmund, a former world number 14, has not won a match on the main ATP Tour this year, succumbing to his eighth straight defeat with the loss against Muller.
In the women's draw, two-time champion Elina Svitolina was beaten by fellow Ukrainian Lesia Tsurenko in only her third top-level match since returning from giving birth to her first child in October.
The pair have been two of the most vocal players when speaking out about Russia's invasion of their country.
Both wore Ukrainian symbols on their kit and sharing an emotional embrace after Tsurenko sealed a 6-4 6-3 win.
Elsewhere, Spanish city Seville has been announced as the host venue for the 2023 Billie Jean King Cup finals.
