Some 3,500 US troops and 1,000 Israeli soldiers have begun a joint military drill, an Israeli military spokeswoman has said.
"Austere Challenge 12 is the largest aerial defence exercise to take place between the two militaries," an Israeli military statement said on Sunday.
Of the 3,500 US personnel involved, around 1,000 will be stationed in Israel, while the rest will operate in Europe and the Mediterranean, Lieutenant General Craig Franklin, a senior US air force officer, told reporters last week.
Troops will train together on Israel's Iron Dome missile defence system, the latest version of the US Patriot and the Arrow anti-ballistic missile system, jointly developed by the two allies.
Command and control functions will be provided by US Navy Aegis cruiser.
The long-planned operation comes as the world grapples with the standoff over Iran's nuclear programme, and as a bloody civil war in Syria threatens to set the region alight, although Israel and US officials have said there is no
Franklin said the operation, which would last "about three weeks", was a defensive exercise unrelated to any other developments in the Middle East.
"While the scenario is driven by the overall situation in the Middle East, AC12 is not related to any specific current event ... nor to any perceived tensions in the Middle East," he said.
The Israeli statement also stressed that the drill was not a response to any events in the region.
"These exercises are part of a planned training schedule that seeks to increase cooperation interoperability between the militaries. Planning for the exercise began over two years ago and is not a response to specific events in the region," the statement said.
The drill will simulate missiles raining down on Israel from Iran, Syria, Lebanon and the Gaza Strip to test its anti-missile batteries.
A US Aegis ballistic missile defence ship is also to participate from the northern Israeli port of Haifa.
The cost of the exercise is around $38m, with Washington covering around $30m of the total.