West Ham will have to come from behind in Germany next week if they are to reach their first European final in 46 years after Eintracht Frankfurt secured a deserved first-leg advantage at London Stadium.
Jarrod Bowen came agonisingly close to snatching a draw for the hosts in stoppage time when his overhead kick from a Declan Rice cross bounced down off the crossbar.
But that would have been harsh on Frankfurt, who were a constant threat on the counter-attack and showed why they had won away at Real Betis and Barcelona already in the knockout stages.
The visitors had the perfect start when Ansgar Knauff scored inside the opening minute.
The Hammers did recover through Michail Antonio's 11th goal of the season - and his first in the Europa League since September - as he bundled home Kurt Zouma's nod down at the far post.
It was Frankfurt who got the winner when Daichi Kamada tapped home after Djibril Sow's low shot was turned into his path.
Until the dramatic finale, a Bowen shot that flicked off the outside of a post and Said Benrahma's dipping second-half effort that flashed narrowly wide were West Ham's most dangerous efforts.
It was a disappointing outcome for David Moyes' men, although having performed brilliantly in Lyon to reach the last four, they do have hope when they travel to Frankfurt for the return.
