The talks are being held in the Iraqi capital, Baghdad, at Iran's request.
They come a day after the UN's nuclear watchdog held talks with Iran to try to gain better access to the regime's nuclear installations.
Iran's Foreign Minister Ali Akbar Salehi says any efforts by Western powers to put pressure on Iran at the talks would be "futile".
But he told a news conference in Tehran on Wednesday that there were reasons to be optimistic about the negotiations.
"The ideas fielded to us speak of the fact that the other side would like to make Baghdad a success. We hope that in a day or two we can bring good news."
Tehran insists its uranium enrichment programme is for peaceful purposes, but the West fears Iran is developing a nuclear weapon.
The five permanent members of the UN Security Council - the US, Britain, France, Russia and China - plus Germany are seeking to persuade Iranian officials to scale back their nuclear programme.
Security is tight, with about 15,000 Iraqi police and troops protecting the venue inside Baghdad's heavily fortified Green Zone.
Continue reading the main story James Reynolds BBC Iran correspondent, in BaghdadThese talks mark a strange reunion - for eight years in the 1980s, Iran fought against Iraq. Then, in 2003, America and Britain led the invasion of Iraq.
US soldiers once fought their way to Baghdad because of suspicions of weapons of mass destruction.
Now, US diplomats come back to the same country to talk about the same subject. This time the country in question is Iran, not Iraq.
No-one expects a breakthrough at this round of talks. Nor do they expect a breakdown either.
Previous talks in Istanbul in mid-April managed to find enough common ground to arrange a further meeting in Baghdad.Correspondents say Wednesday's talks will put these renewed efforts to the test.
A senior Western official quoted by Reuters said that the six - led by EU foreign policy chief Catherine Ashton - would make Iran "a detailed proposal that will include confidence-building measures".
However, no details were given on what those measures might be.
Analysts say the main goal of the six powers will probably be an Iranian agreement to shut down the higher-grade uranium enrichment programme that it launched in 2010.
SanctionsIran has since expanded the enrichment process at an underground plant at Fordo, outside the northern city of Qom.
Continue reading the main storyUK ministers are discussing not just the possibility of a military confrontation but what role, if any, Britain might play and whether any involvement would be legal.”End Quote On Tuesday, International Atomic Energy Agency (IAEA) chief Yukiya Amano said an agreement with Iran over nuclear inspections was expected "quite soon" following his recent talks in Tehran.
He said the deal could increase Tehran's co-operation with IAEA investigations into its atomic activity.
The IAEA wants its inspectors to have greater access to Iranian sites, nuclear scientists and documents.
The EU, the US and the UN have all imposed sanctions on Iran over its nuclear programme.
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