"In the context of the Arab Spring and US commitments to support nonviolent movements for democracy, now is the time for US leaders to show their support for Saudi women's rights," said the letter to the chief US diplomat.
"We were encouraged to see media reports that US diplomats have quietly pressured the Saudi government to give women the right to drive.
"But given the recent arrests of women trying to drive, now is the time for the US to show its muscle and make that pressure public," it continued.
The petition comes after Manal Sharif, a 32-year-old computer-security consultant, was arrested on May 22 after posting on YouTube a video of herself driving her car around the eastern Saudi city of Khobar.
Many women are said to have followed her example.
"We write to ask that you (Clinton) make a public statement supporting Saudi women's right to drive," the female activists said.
"We do not make this request lightly, but we believe that you making a public statement of support for Saudi Arabia opening the country's roads to women would be a game changing moment."
The letter said the ban on women driving in Saudi Arabia means they miss medical and other important appointments and are prevented from carrying out basic errands in the absence of a good public transportation system.
"Our lack of this basic right to drive our own cars has been repeatedly exploited by abusive fathers, brothers, husbands and even hired drivers," it added.
"Just this week, a Saudi woman reported she was raped by her driver."
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