Already beaten by Monaco in their first game at their adopted home in September, Tottenham were rocked at Wembley.
Tottenham suffered more Champions League misery at Wembley as a 1-0 defeat against Bayer Leverkusen on Wednesday left them in danger of failing to qualify for the last 16.
Mauricio Pochettino's side are playing their European matches at Wembley this season while White Hart Lane is being redeveloped and the temporary move has proved a disaster for the north London club.
Already beaten by Monaco in their first game at their adopted home in September, Tottenham were rocked at Wembley again as Kevin Kampl bagged Leverkusen's second half winner.
Since winning their first match at the rebuilt English national stadium against Chelsea in the 2008 League Cup final, Tottenham have now lost six consecutive games at Wembley.
It could have serious consequences for Tottenham's Champions League campaign as Leverkusen's first ever win in England lifted them above the Premier League team into second place in Group E.
Tottenham, without a win in their last six games in all competitions, are two points behind Leverkusen with two games remaining against Monaco and CSKA Moscow.
"We don't have the freedom to play and show real quality. After two games at Wembley, both have been poor. It is not an excuse, it is the truth," Pochettino said.
"We need to improve and change some things. We are in a bad moment."
Leverkusen coach Roger Schmidt added: "I'm very happy because this was a very difficult away game and we won it.
"Tottenham are unbeaten in the Premier League so that makes it even more special."
Pochettino had called on his players to embrace the Wembley experience and an English club record home crowd of 85,512 packed in to support them.
But a series of sloppy Tottenham passes around their own penalty area almost presented Leverkusen with a chance in the first minute and the lethargy gripping Pochettino's side wasn't limited to the defence.
With Harry Kane still not fit enough to feature after his ankle injury, Son Heung-min started up front in place of Vincent Janssen.
Son had scored five times this season, but the South Korean was starved of service against his former club.
An injury to Mousa Dembele, who was replaced by Janssen, did little to improve Tottenham's momentum.
It took over half an hour before Tottenham had a shot when Christian Eriksen's strike was pushed away by Leverkusen goalkeeper Bernd Leno.
Leverkusen's players trained among the joggers and dog walkers of London's Regent Park on Wednesday morning and that low-key build-up seemed to relax them after a difficult spell in the Bundesliga.
They should have been in front just before the break when Kyle Walker carelessly lost possession to Julian Brandt on the edge of the penalty area.
When Brandt picked out Javier Hernandez a goal seemed certain, but the former Manchester United striker's shot was deflected away by Jan Vertonghen.
Dele Alli had the ball into the net on the stroke of half-time, but the Tottenham midfielder's effort was ruled out for a foul by Janssen in the build-up.
Pochettino's team emerged in more vibrant mood after half-time and Alli appealed in vain for a penalty when he was sent sprawling by Omer Toprak's lunge.
Eriksen dragged his shot narrowly wide while Tottenham continued to protest and the hosts threatened again when Walker drilled a low strike past the far post.
More negligent Tottenham defending, this time from Eric Dier, gifted Hernandez with another good chance, only for the Mexican to let him off the hook with two tame shots.
Leverkusen finally made Tottenham pay for their error-strewn display in the 65th minute.
Charles Aranguiz's shot deflected off Ben Davies and then Walker before trickling through to Slovenia winger Kampl, who slotted past Lloris from close-range.
Dier smashed a free-kick against the crossbar in the closing moments, but that was the extent of Tottenham's tepid and ultimately fruitless push for an equaliser.