Khamenei has not publicly endorsed the deal reached with world powers in July, which was a political victory for the moderates led by President Hassan Rouhani. Hardliners inside Iran are still trying to put breaks on the agreement.
In an address to Revolutionary Guards Navy commanders, Khamenei said talks with the United States brought only disadvantages to Iran.
"Negotiations with the United States open gates to their economic, cultural, political and security influence. Even during the nuclear negotiations they tried to harm our national interests whenever they had a chance," Khamenei was quoted as saying on his website.
Khamenei's comments put him at directly at odds with Rouhani, who is hopeful of normalising relations with the West and who has repeatedly said his government is ready to negotiate "with anyone" to resolve regional issues.
The July deal curbs Iran's nuclear program in return for sanctions being lifted. The West feared Tehran was seeking to develop a nuclear weapon, suspicions Iran has denied.
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