Hundreds of Christian protesters gathered outside the Wales Millennium Centre (WMC) as the curtain went up on Jerry Springer - The Opera.
Hundreds sang hymns as ticket holders arrived for the show
The hymn-singing demonstrators were said to represent one of the largest protests yet in a tour which has encountered repeated opposition.
But the Cardiff concert hall said more tickets had been sold for its Welsh run than anywhere in the 21-venue UK tour.
Managers said it was their job to put on performances that were challenging.
Some Christians claim the award-winning show, which features Jesus, Mary and God as characters and parodies the American Jerry Springer TV show, is offensive and blasphemous.
More than 100 church leaders signed a letter calling for the cancellation of the show, which features up to 300 swear words.
Archbishop of Wales Barry Morgan said the opera deliberately set about inciting religious hatred.
"The producer of this opera says that if he manages to incite religious hatred then the opera has done its job," he said. "I think that is a terrible intention for an opera to have.
"I have seen bits of it on the television and it really is blasphemous. It really does belittle the Christian faith and if something like this was produced about the Prophet Muhammad there would be a riot."
The Archbishop of Wales says the show belittles the Christian faith
The West End production of Jerry Springer - The Opera, starring David Soul, was seen by 425,000 people. It was watched by an audience of 2.4m when it was broadcast on BBC Two in January 2005.
The BBC received a record 63,000 complaints as well as many messages of support in response to its content.
More than 1,200 tickets were sold for the opening night of the show's six-day run in Cardiff, which ends on 17 June.
The WMC said it had met church leaders to discuss the show, and art should both challenge and entertain.
But in a statement released in early June, the WMC said it was committed to staging art that would "push the boundaries".
Judith Isherwood, chief executive of the WMC, said: "It should be seen by audiences much further afield than the West End.
"So when the opportunity came up to be part of the national tour, we were one of the first to say we would like to take that show."
The centre's directors have agreed to host a debate on the show which they say will allow everyone to air their views.
The protesters said they would continue their stand throughout the Cardiff run.