Southampton wasted the chance to take a significant step towards the Europa League's knockout stages with a disappointing 1-0 defeat at Inter Milan.
Their manager Claude Puel gambled in making six changes to his team but on an evening when they could have built their lead at the top of Group K, they fell to third as Antonio Candreva's goal and Inter's first points kept the Italians in contention to progress.
That Inter were reduced to 10 men meant further frustration in what had been such a glamour tie for Puel's team. The result, meanwhile, puts greater pressure on their remaining three fixtures.
Even with the success Puel has had it seemed strange to rest Charlie Austin, Steven Davis, Jordy Clasie, Jose Fonte and Nathan Redmond for such an occasion.
The latter had not even travelled to Italy, and had been as instrumental as the other four in the convincing display that secured Sunday's 3-1 defeat of Burnley.
In their absence, Jay Rodriguez, Shane Long, James Ward-Prowse, Pierre-Emile Hojbjerg and Maya Yoshida were selected. There was also a full debut at left-back for one-time winger Sam McQueen, 21, who replaced the injured Matt Targett in Puel's sixth change.
Perhaps a somewhat disjointed performance was therefore inevitable, but Rodriguez may reflect that had he shown greater confidence this could have been an important win.
He is still to truly recover from the anterior cruciate ligament injury he suffered in 2014 when producing his finest form, and at times it showed.
Through on goal in the ninth minute, he was in a fine position to score but instead hesitated and was dispossessed by Miranda. Later in the first half he again conceded possession when he should have shot.
Southampton came closest to scoring in the 28th minute, when McQueen's cross was spilt by Samir Handanovic against Long. The ball then rolled past the goalkeeper and towards the back of the net, before Yuto Nagatomo raced back to clear.
A minute later, Ward-Prowse powerfully shot just over the crossbar from the edge of the area after a cut-back from Cuco Martina. Inter's only notable response had been a 41st-minute shot from Eder, also from the edge of the area, that he dragged wide of the left post.
Austin was introduced as a 48th-minute substitute when Long indicated an injury, but if there was optimism his directness would prove the difference it soon vanished when Inter took the lead.
A Rodriguez header had been disallowed for a foul when, from nowhere and with little threat, Davide Santon - once of Newcastle - sent a left-wing cross into Southampton's area. From there, Candreva produced the most powerful of finishes into the roof of the net beyond Forster. Southampton already looked defeated.
Marcelo Brozovic's dismissal, for a second yellow card after a foul on Hojbjerg, presented an opportunity but the closest the visitors came to an equalising goal was wasted in the 82nd minute by Virgil van Dijk.
Ward-Prowse's classy cross left the defender with the simplest of chances from directly in front of goal but he sent a casual finish towards Handanovic, allowing the goalkeeper to easily save.