State TV quoted Ayatollah Ali Khamenei as saying Western leaders must prove they are not "accomplices" in a "big crime."
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Such an appeal falls into the major cultural divide over the film. US officials say they cannot limit free speech and Google Inc. refuses to do a blanket ban on the YouTube video clip. This leaves individual countries putting up their own blocks.
Khamenei noted that some nations place restrictions on expression deemed hate speech, such as banning Nazi-related sites, or legislating protections for gays or lesbians.
"How there is no room for freedom of expression in these cases, but insulting Islam and its sanctities is free?" Khamenei was quoted as saying.
Separately, Iran's Foreign Minister Ali Akbar Salehi said Iran will send a protest letter on the film to the UN Secretary-General Ban Ki-moon.
Iranians have staged several demonstrations against the film, but none have been violent. Crowds gathered last week in front of the Swiss Embassy, which looks after American diplomatic interests in Iran.
A semi-official religious foundation also increased a reward it had offered for the killing of British author Salman Rushdie to $3.3 million from $2.8 million over his book "The Satanic Verses," which was considered blasphemous by Iranian leaders.
A 1989 fatwa, or religious edict, was issued against Rushdie by Iran's late leader Ayatollah Ruhollah Khomeini, but Iranian authorities have since distanced themselves from the order.