Senior US and Nato officials are attending the ceremony in Deveselu, southern Romania. The US says the Aegis system is a shield to protect Nato from short and medium-range missiles, particularly from the Middle East.
"As long as Iran continues to develop and deploy ballistic missiles, the United States will work with its allies to defend NATO," said U.S. Deputy Defence Secretary Robert Work, standing in front of the shield´s massive gray concrete housing that was adorned with a U.S. flag.
Despite Washington´s plans to continue to develop the capabilities of its system, Work said the shield would not be used against any future Russian missile threat. "There are no plans at all to do that," he told a news conference.
The officials also stress the shield is not directed against Russia. But Russia sees it as a security threat - a claim denied by Nato.
Relations between the West and Russia have deteriorated since Moscow´s annexation of Ukraine´s southern Crimea peninsula in 2014.
Russia is also accused of arming separatists in eastern Ukraine and sending its troops there - a claim denied by the Kremlin.
Nato Secretary General Jens Stoltenberg and other senior officials from the military alliance are at the opening ceremony at an old Romanian air base in Deveselu.
Nato and US officials say the system has been developed to track and intercept missiles fired from a "rogue" state. In the past Iran was mentioned in that context, but the US has also had North Korea in mind.
For years the US has been testing the Aegis system on warships too.
Russia´s foreign ministry warned on Wednesday that the system violated a treaty on nuclear forces. A ministry statement quoted by Interfax news agency said it was a breach of the Intermediate-Range Nuclear Forces (INF) Treaty, signed in 1987.
"This decision is harmful and mistaken, because it is capable of upsetting strategic stability," said Mikhail Ulyanov, head of the Russian foreign ministry´s department for proliferation and arms control issues.
An incoming missile would be destroyed in space, before it could re-enter the Earth´s atmosphere.
On Friday, another phase of the project will be launched in Poland with a groundbreaking ceremony at Redzikowo, near the Baltic Sea. Aegis missiles are to become operational there in 2018.
Mr Ulyanov said Russia´s interests "are being affected in a direct way by this", the Americans´ MK-41 launch system could also be used to fire cruise missiles, not just air defence missiles.
"From our viewpoint this is a violation of the Intermediate-Range Nuclear Forces Treaty," he added.