Glentoran had defender Jamie McGovern and keeper Elliott Morris sent-off as they lost to a late goal in Macedonia.
McGovern got a straight red for a foul in the 14th minute and Boban Jancevski netted the penalty for Renova.
But Glentoran remained well in contention and skipper Colin Nixon equalised by heading in from Kyle Cherry's corner just before half-time.
Muarem Bajrami scored the winner and then Morris was dismissed for a second yellow card.
Replacement keeper Aaron Hogg could not come on as the Glens had already used their three allowed substitutions.
Bajrami struck in the 87th minute just when it was beginning to look like the Belfast side would come away with a draw.
The second leg takes place at Glentoran's Oval ground on 7 July.
Despite the defeat, Scott Young's men will feel they have a fair chance of getting through a round in Europe, something they have not done since beating Finnish side Allianssi in the 2004 Uefa Cup.
They were without new signings Aidan O'Kane and Stephen Carson and other key players Jimmy Callacher and David Howland.
Nixon admitted after the game that he "didn't know much about" his goal.
"I just managed to get my head on it and it went in.
"We were fighting hard and managed to come in level at half-time - it's just unfortunate that we ended up losing but the tie is still very much alive," said Nixon.