Although they exercised their customary domination of possession, Barca again looked short on ideas in the final third of the pitch and Real strolled to a 3-1 victory at the Nou Camp that put them through to May's final 4-2 on aggregate.
Jose Mourinho's side, organised in defence and clinical in attack, appeared to find it just as easy to keep Barca at bay as AC Milan did when they beat the Catalan club 2-0 in last week's Champions League last 16, first leg.
However many passes Xavi, Andres Iniesta, Sergio Busquets and their team-mates strung together they were too predictable and were unable to provide Lionel Messi with the service that has made the World Player of the Year such a lethal goal scorer.
Vilanova, who stepped up from assistant coach to succeed Pep Guardiola at the end of last season, needed a second round of surgery in December following an operation to remove a tumour from his saliva glands in November 2011.
His assistant Jordi Roura has temporarily taken over and although the pair are in constant contact there is little doubt that Vilanova's absence is far from the ideal situation at a crucial period of the season.
The contrast with Real is significant.
Mourinho brings the authority of a two-times Champions League winner who has experience across Europe to their bench while Roura, a former Barca player, has never had a top coaching job at the highest level.
"Without taking anything away from the work of the rest of the coaching staff there is no doubt that we miss Tito Vilanova," Barca president Sandro Rosell told Spanish broadcaster Canal Plus after the Real defeat.
"He is our coach, our leader," he said, confirming that he would be travelling to New York to visit Vilanova this week.
"Imagine any institution, any company, any factory without their chief of production.
"That's why it's important that we visit him and check how he is getting on.
"The priority is his health ahead of any match, any victory and any trophy that we might want to have in our cabinet."
Barca's bid to repeat their 2009 treble of titles in the Champions League, La Liga and Copa del Rey is now over and they face a tough task in overturning the two-goal deficit at home to Milan on March 12.
However, they appear to have a fourth La Liga title in five years within their grasp.
They are 12 points clear of second-placed Atletico Madrid ahead of Saturday's trip to play champions Real at the Bernabeu with Mourinho's side a further four points back in third.
"If we only won the league it would still be a very good season," Rosell said.
"It's the competition that rewards consistency and it's the trophy that everyone wants before the season starts.
"The others are knockout competitions and are more difficult because if you play one poor match you are out.
"Winning the league proves you are the best team."
- Sports & Recreation
- Champions League
- Jose Mourinho
- Tito Vilanova