Bafetimbi Gomis struck a late equaliser for Lyon but Real Madrid will be favourites to progress to the Champions League quarter-finals for the first time in seven years thanks to Karim Benzema's away goal in a 1-1 draw.
Benzema, who joined Madrid from Lyon in 2009, scored just seconds after coming on as a 64th-minute substitute to put Madrid ahead in Tuesday night's last-16, first leg tie.
Madrid could not hold onto that advantage with Gomis volleying home in the 83rd minute, but Jose Mourinho's men will fancy their chances in the second leg at the Bernabeu, where they have won their last 22 competitive games.
Madrid's first serious effort came from Angel Di Maria's long-range drive on the half-hour mark, but that was saved relatively comfortably by Hugo Lloris despite bouncing awkwardly just in front of the Lyon goalkeeper.
Lloris was given a tougher test moments later when Cristiano Ronaldo tried his luck with a free-kick, the goalkeeper diving to his right to parry.
The best chance of the opening period arrived in the 35th minute when Madrid goalkeeper Iker Casillas pushed out a cross and Gomis latched onto the loose ball inside the area, but his shot was deflected over the bar for a corner.
Madrid might not have been in top gear in the first half, but they started the second period in devastating fashion and hit the woodwork twice within five minutes of the restart.
Ronaldo's free-kick from the side of the area beat Lloris before coming back off the far post and Sergio Ramos' looping header from Mesut Ozil's corner then struck the bar with Lloris again beaten.
Soon after that Mourinho sent on Benzema for Emmanuel Adebayor, a move which paid immediate dividends as the France international scored just moments later. Ozil and Ronaldo combined on the edge of the area to put in Benzema, who powered his away across the centre of the box before squeezing his shot through Lloris' legs.
That looked set to be the winner, but Lyon fought back and equalised with seven minutes to go. A free-kick was deflected up into air and Cris climbed highest to head the ball into the path of the unmarked Gomis, who volleyed past Casillas to earn his side a draw.
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