Speaking before the Saban Center for Middle East Policy in Washington, Panetta stressed that the key was "working together," adding that a military strike could have severe economic consequences worldwide.
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Panetta said a strike could disrupt the already fragile economies of Europe and the United States, trigger Iranian retaliation against US forces, and ultimately spark a popular backlash in Iran that would bolster its rulers.
It also may not be effective, he said, citing assessment from Israeli sources, adding that a strike might set back Iran's nuclear program by one to two years "at best." He said the US will continue to focus on sanctions as a means to curb Iran's suspected nuclear weapons ambitions.
Panetta identified Iran as "the most significant national security threat facing the United States, its allies and partners in the region…No greater threat exists to the security and prosperity of the Middle East than a nuclear-armed Iran," he said.
Washington, he continued, was committed to curbing Iran's "destabilizing activities, particularly those that could threaten the free flow of commerce throughout this vital region. That is a 'redline' for the United States."
Panetta said he was convinced that sanctions and diplomatic pressure were working: "You always have the last resort ... of military action. But it must be the last resort, not the first.
"That's a responsibility I take very seriously, because when it comes to the threat posed by Iran, the president has made it very clear that we have not taken any options off the table," Panetta said.
He finally warned about engulfing the region in war: "Lastly I think the consequence could be that we would have an escalation that would take place that would not only involve many lives, but I think could consume the Middle East in confrontation and conflict that we would regret," he said.
AP and Reuters contributed to this report
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