Khamanei said during a Sunday evening ceremony breaking the daily Ramadan fast he was generally opposed to talks with the United States except on regional issues.
"I am not optimistic about negotiation with the United States, although I have not rejected negotiations over certain issues such as Iraq in the past years," he was quoted by state-funded broadcaster Press TV as saying.
Iranian President-elect Hassan Rouhani, a former nuclear negotiator, said he would embrace engagement as part of his foreign policy platform when he takes office next month. He ran as a moderate in June elections when compared to conservative challengers aligned more closely with Khamanei.
Khamenei has ultimate say over Iranian affairs. He said he believes in international engagement so long as the Islamic republic is respected.
The U.S. government suspects Iran is pursuing technology needed to manufacture a nuclear weapon, an allegation the Iranian government denies.
Tehran said it was interested in holding multilateral nuclear talks in Kazakhstan. Two rounds of talks between Iran and the five permanent members of the U.N. Security Council plus Germany ended with little progress early this year.