Lyon have won three and drawn four of their eight meetings since 2005 and inflicted a painful defeat on the nine-times European champions in the last 16 in March 2010 when a 75th-minute goal stunned the Bernabeu and sent them through 2-1 on aggregate.
The teams meet again in Group D on Tuesday and Real captain Iker Casillas said he hoped the Lyon demons had now been banished for good.
"Last year... it was important to get through to the quarter-finals," goalkeeper Casillas told a news conference on Monday as he reflected on a campaign that was finally ended by Barcelona in the last four.
"Our overall record against Lyon is negative but last year we banished the ghosts both of Lyon and getting knocked out at the last-16 stage.
"Several years of not being up to scratch in European competition does make you more concerned but last year we made it to the semis and let's see if we can achieve more this time around," Casillas added.
President Florentino Perez has spent hundreds of millions of euros on players such as Cristiano Ronaldo, Kaka and former Lyon striker Karim Benzema as he bids to realise his dream of what has become known in Spain as "la decima" or "the 10th."
Benzema scored home and away for Real in last season's 4-1 aggregate win over his former club and has been in impressive form this term.
The Frenchman's strike partner Gonzalo Higuain is also in the middle of a purple patch having netted three hat-tricks in two weeks, two in La Liga and one for Argentina.
"I am not going to say whether Higuain or Benzema is playing. Or if they both play or neither of them," he told reporters.
The former Chelsea coach returns to Real's bench on Tuesday after serving a three-match ban imposed by UEFA for comments he made after last season's semi-final defeat.
"That's old history," said Mourinho when asked about the ban. "This is a new Champions League competition and a new season.
"Let's see if we can do better this time."
