"No one should see our negotiating team as compromisers," Khamenei, Iran's top decision-maker on its nuclear drive, was quoted as saying on his official website."I am not optimistic about the (nuclear) negotiations but, with the grace of God, we will not suffer losses either," he added.
A new round of talks between Iranian negotiators and representatives from the so-called P5+1 group of world powers is scheduled in Geneva for November 7 and 8. The second meeting since moderate President Hassan Rouhani took office in August, the talks are aimed at curbing Iran's sensitive nuclear work in exchange for a relief from international sanctions strangling Iran's economy.
All decisions on the nuclear programme, which the West suspects is masking a military drive despite repeated Iranian denials, rest with Khamenei.
"All the better if the negotiations bear fruit but if there are no results, the country should rely on itself," said Khamenei while criticising the US policy of approaching the talks on two fronts of sanctions and diplomacy.
"The Americans smile and express desire for negotiation; on the other hand, they immediately say that all options are on the table," he said. "We should not trust a smiling enemy."
In March the supreme leader warned the United States was "not interested in a nuclear settlement," and in July he said American officials were "not trustworthy".
The talks between both Iranian negotiators and P5+1 representatives from the United States, Britain, France, China and Russia plus Germany were restarted last month in Geneva.
Both sides say they see the new push as substantive.
Foreign Minister Mohammad Javad Zarif, who oversees Iran's negotiating team, said he hoped the meeting would usher in a "new phase" of relations with between Tehran and the international community.
But Zarif's team has faced criticism at home from hardliners wary that the negotiators could compromise Iran's nuclear work.
The disapproval peaked in late October when anti-American posters questioning Washington's sincerity in the talks went up on Tehran's streets, before the authorities removed them.
Khamenei on Sunday warned against such criticism, while expressing support for the "difficult" task at hand.
"No one should see our negotiating team as compromisers," he said.
"They have undertaken a difficult mission and no one should undermine an agent on a mission."
The administration of US President Barack Obama has said it is important to test the sincerity of Iran's promise to hold serious discussions on its nuclear drive, while promising to keep its allies, including Israel, informed about the process.
Khamenei was also critical of the close US alliance with the Jewish state, whose existence the Islamic republic does not recognise.
"The Americans have the highest indulgence towards the Zionists and they have to. But we do not share such indulgence," he said.
"The Zionist regime is an illegitimate and bastard regime," he said.
His remarks reaffirmed Tehran's position on Israel, which has been toned down since the departure from office of hardline former president Mahmoud Ahmadinejad.