Envoys from the US, UK, France, China, Russia and Germany hope the talks will halt rising regional tension.
Iran says its nuclear programme is peaceful, but critics suspect it of seeking to develop nuclear weapons.
Israel has hinted in recent months that it could carry out a pre-emptive strike on Iran to prevent that happening.
The talks are the first to be held between Iran and the world’s major powers for 15 months.
The envoys are setting the bar pretty low – they do not expect detailed, substantive proposals from either side.
What they want to see is whether Iran is ready to seriously engage and, if that happens, there may be another round of talks in four to six weeks time.
Michael Mann, spokesman for EU foreign policy chief Catherine Ashton, said the Istanbul talks had started in a “positive atmosphere”, adding: “There is a desire for substantive progress.”
The six world powers, known collectively as the P5+1, hope the talks will at least cool tensions.
Russia said they had to be “constructive”, and warned both sides not to “overblow the differences” between them.
“We really need to find a middle course,” said Deputy Foreign Minister Sergei Ryabkov.
“The negotiations are about renewing confidence.”
US President Barack Obama has described this as a “last chance” for diplomacy to work, while Secretary of State Hillary Clinton said Iran had to “demonstrate clearly in the actions they propose that they have truly abandoned any nuclear weapons ambition”.
But one source close to the Iranian delegation told Agence France-Presse: “So far the Iranian delegation finds the Western position … disappointing and discouraging.”
On Thursday, Iranian President Mahmoud Ahmadinejad said his country was “standing firm on its fundamental rights and under the harshest pressure will not retreat an iota from its undeniable right”.
The P5+1 group hopes eventually to persuade Iran to reduce its enrichment of uranium and fully open up its nuclear facilities to inspectors from the International Atomic Energy Agency (IAEA).
There are suggestions that the stringent sanctions on Iran could be reduced if it complies with the requests.
The last series of international talks broke down in January 2011 after the parties failed to agree on any issues.
Since then, the IAEA expressed concern that Iran had failed to co-operate with its inspectors and had carried out activities “relevant to the development of a nuclear explosive device”.
Israel, which believes a nuclear-capable Iran would be a direct threat to its security, has warned that time is running out to prevent that outcome.
Prime Minister Benjamin Netanyahu has said he would never allow Israelis to “live in the shadow of annihilation”, and hinted his country is ready to strike Iran’s nuclear facilities if diplomacy does not work soon.
President Barack Obama has warned against “loose talk of war”, while stressing that all options remain open.
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