The city is preparing to hand over control of the central St Isaac's Cathedral -- Russia's largest -- to the Orthodox Church after decades as a museum.
But the decision has sparked a furious row, pitting clerics against locals who feel aggrieved the city is handing over a key tourist asset to the Church without public consultation.
The imposing domed cathedral built in the 19th century is popular with tourists who climb up onto its roof for a spectacular view.
After Russia's 1917 revolution, the atheist Bolsheviks took over churches, stripping them of valuables and using them as factories or storerooms.
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St Isaac's Cathedral served for a time as a Museum of Atheism.
In the latest round of protest action, some 400 clerics and believers on Sunday held a procession around the cathedral carrying crosses.
Among those taking part was MP Vitaly Milonov, who spearheaded controversial anti-gay legislation.
He said that keeping the cathedral as a museum is "an infringement of the rights of believers".
Galina Raiskaya, 57, stressed the cathedral is a "house of prayer."
Hours later, around 2,500 opponents of the Church takeover formed a circle around the cathedral in the biggest protest yet.
They carried placards with slogans including "Russian Church: Hands off Isaac's" and "Russia is a secular state," and chanted "Museum! Museum!"
"The Church, they're just parasites who are after money," said one demonstrator, 50-year-old Natalya Gorokhova.
The protest's organiser, lawmaker Boris Vishnevsky of the Yabloko liberal party, said "the fact that there are so many of us will force the authorities to back down."
The "no" campaign has been backed by key cultural figures, notably the director of the nearby State Hermitage Museum, Mikhail Piotrovsky, who wrote to Russian Orthodox Patriarch Kirill asking him to delay the handover to cool tensions.