Fire crews were called to the corner of North Road and Saint James Close at 6.40am and arrived to find the 123-year-old church engulfed in flames.

Twelve appliances and about 60 firefighters battled the blaze, but were unable to stop the roof from collapsing, a Metropolitan Fire Brigade spokesman said.

"I can tell you the building has been severely damaged and there are concerns about structural stability, but that's yet to be assessed," MFB spokesman Keith Robinson said.

Mr Robinson said the fire was brought under control about 7.30am.

He said it was too early to say what caused the fire.

Power to neighbouring homes was turned off. Pat Burke, who lives opposite the church, said she heard sirens at 6.30am.

"I opened up the blinds and looked and all I could see was orange and the smoke," she said.

"I immediately ran out to see if we were at risk."

Parishioners said it would be a test for their new parish priest, Reverend Michel Corriveau, who only came to the church at the start of the month.

"When he started, he was so enthusiastic, everyone was really excited," Annie O'Donoghue said from the scene.

"For this to happen, he's got his job cut out for him now."

Mrs O'Donoghue lives nearby and woke to flames billowing from the roof.

She said much history had been lost.

"We got married here, my husband grew up in the parish, and our five children have been baptised here," she said.

Elwood resident Bob McEwan said he had been coming to the church since he was a child. Mr McEwan said his mother's funeral had been held at the church two years ago.

"My auntie had her funeral only two weeks ago, so there's a huge emotional and spiritual attachment to it," he said. "It's a magnificent church."

North Road was closed in both directions, while neighbours gathered on the street, some barefoot, watching smoke pour into the air.

A thick plume of smoke was visible from as far away as Williamstown, on the other side of Port Phillip Bay. 

CHURCH FIRE " Historic St James, Brighton, now full involved and visible from the West Gate bridge (via @RossAndJohn) pic.twitter.com/2HWN0sJTfP — #BuskingMelbourne (@3AW693) March 29, 2015

No one was injured in the fire but paramedics were at the scene on standby, an Ambulance Victoria spokesman said.

Fire investigators had not yet been able to gain access to the church, with engineers still determing whether the building was structurally sound enough to allow entry, but MFB's Costa Katsikis said early indications were the building would not need to be demolished.

"It is surprising (given it was) a significant fire with a large fire load," he said.

"They're looking at every effort to preserve the building."

Police arson chemists will assist the MFB with the investigation.

The Catholic church dates back to 1892, and a small wooden church stood in the same spot for at least 10 years before that, according to the church's website.

It was heritage listed as a building of state significance in 1984.

Catholic Archdiocese of Melbourne communications director Shane Healy said the building's interior had been gutted and artefacts, including its old "magnificent" organ, destroyed.

"The parish priest, Father Michel, and a lot of parishioners are very, very upset. This church dates back to the absolute early history of the Catholic Church in Melbourne," Mr Healy said.

"It really was the living, breathing heart of the early church in Melbourne."

He said they hoped the church's facade could be saved.

The fire occurred in the lead-up to one of the busiest times of year for the parish, with its Easter services usually attracting thousands.

Mr Healy said services would be moved to the Star of the Sea chapel next door.

He said it was "too early" to tell whether insurance would cover the damage bill, which was still unknown.

He said there was nothing to make him fear it was a suspicious fire.

The Victorian Heritage Database says the church's nave is of interest "for the facade, with traceried window … and the large sexfoil clerestory windows."

"The interior includes an unusually elaborate decorative scheme of 1934 in Opus Sectile mosaic covering the walls of the apse," the database says.

The church's pipe organ dates from 1902 and was heritage listed in 1992. The church's bell ringers arrived this morning to determine whether the church's six bells and 11 hand bells, worth tens of thousands of dollars, were still intact.

Lead bell ringer, tower captain Pat Cole, said the church was a "huge part" of Brighton. "For me, it was a haven," he said.

#stjames brighton #fire @7NewsMelbourne pic.twitter.com/PrmqqCSAVd — CameronBaud7 (@CameronBaud7) March 29, 2015

More to come.