Roma had taken the lead through a Paulo Dybala penalty, but Real Betis turned it around to win 2-1 at the Stadio Olimpico, with Nicolò Zaniolo sent off for a petulant foul in stoppages.
The Giallorossi needed a victory to go top of the group, having lost to Ludogorets and beaten HJK, while Betis came in with a perfect record. Lorenzo Pellegrini, Rick Karsdorp and Georginio Wijnaldum were injured, with Tammy Abraham returned to the starting XI. The Spaniards missed Juanmi, but had ex-Serie A players Luiz Felipe, German Pezzella and Joaquin.
It was a bad start, because within five minutes Zeki Celik had to come off with a knee injury, replaced by Leonardo Spinazzola.
Rui Patricio parried a Sergio Canales snapshot, then Nabil Fekir thumped the base of the near post from the edge of the box.
However, Fekir went off with a muscular injury, so Betis too had to make an emergency change in the first half.
A Roma corner skimmed the head of Roger Ibanez and Aitor Ruibal had his arm out-stretched and raised to charge it down for an inevitable penalty, awarded after the VAR on-field review. Paulo Dybala sent Claudio Bravo the wrong way to convert.
Luiz Henrique saw his strike smothered after wrong-footing Ibanez, but Guido Rodriguez did equalise with a ferocious daisy-cutter from distance that fizzed into the near bottom corner.
Zaniolo met a cross from the right and smashed it against the underside of the bar from close range, then the move continued and Bravo flew to palm a Dybala volley over.
After the restart, there was a huge save on Bryan Cristante from point-blank range on a chaotic corner, while Zaniolo had a shot smothered at the near bottom corner.
Roma were the better team in the second half, after a difficult first period, as Bravo got his fingertips to a dangerous Nicola Zalewski roll across from the right.
However, Betis took the lead with their first chance in quite a while, Rodri’s cross finding Luiz Henrique to tower above Spinazzola at the back post and send a looping header over Rui Patricio.
It got even worse for Roma, as Zaniolo lost his temper and was sent off for a truly idiotic kick off the ball, meaning he will be suspended for the return fixture.
Roma 1-2 Real Betis
Dybala pen 34 (R), Guido Rodriguez 40 (B), Luiz Henrique 88 (B)
Sent off: Zaniolo 93 (R)