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Cristante steered home in the opening seconds of injury time to decide the game, latching onto an Edin Dzeko cutback and striking sweetly into the far corner.
And that proved to be the decisive moment of the match, after Cengiz Under and Nicolo Zaniolo had earlier grabbed goals for the Giallorossi.
Timothy Weah opened the scoring early on for the hosts, while Luiz Araujo's finish with 20 minutes remaining looked to have set up the draw - at least until Cristante got on the ball in the dying moments.
In contrast to Wednesday's win over Perugia, coach Paulo Fonseca opted not to rotate his side significantly in this one - sticking with the XI he started with until the final 20 minutes of the match.
It was Lille who looked livelier in the first half, although that was perhaps to be expected with the French season set to start next weekend. And they eventually took advantage through Weah, who slotted home after Pau Lopez had parried away Jonathan Ikone's initial attempt.
But the Giallorossi came out strong in the second half and equalised through Cengiz, who followed Dzeko's incisive run in behind the defence and was on hand to slot home from the striker's cutback.
That formula would basically be repeated for Cristante's winner, too. Before that it was Zaniolo who got on the scoresheet - the midfielder seeing his initial attempt from Kolarov's low cross deflect off the crossbar, but reacting fastest to turn home the rebound.
Araujo's smart finish was perhaps against the run of play - and perhaps influenced by the flurry of Roma subs that happened around the same time - but, with a draw then looking almost nailed on, there was still time for the Giallorossi, thanks to Cristante, to return to Italy with an extra spring in their step.
Roma XI to face Perugia: Pau Lopez; Florenzi (Spinazzola), Fazio, J. Jesus, Kolarov; Diawara (Pellegrini), Cristante; Cengiz (Antonucci), Zaniolo, Kluivert (Perotti), Dzeko.
See more photos from the game in our gallery below!
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