Donald Trump has signed an executive order to formally withdraw the United States from the Trans-Pacific Partnership deal, the TPP.
It undoes decades of economic policy work to lower trade barriers across 12 countries.
In an Oval Office ceremony, White House Chief of Staff Reince Priebus handed the documents to Mr Trump.
Mr Trump also signed a federal hiring freeze, but exempted the military.
He also cut funding to non-government organisations which perform abortions overseas.
But the TPP was perhaps the most significant item on the agenda of his first official working day as US President.
Before signing, Mr Trump told US business and manufacturing leaders he was in favour of fair trade, not free trade.
"You want to sell something into China and other countries, it's very, very hard. and in some cases its impossible - they won't even take your product. But when they do take your product, they charge a lot of tax, so I don't call that free trade, what we want is fair trade."
The TPP agreement has been signed - but not yet ratified - by Japan, Malaysia, Vietnam, Singapore, Brunei, Canada, Mexico, Chile, Peru, Australia and New Zealand.
The bloc of 12 nations is currently responsible for 40 per cent of world trade, with a combined population of about 800 million people.
The deal aimed to deepen economic ties between these nations, slashing tariffs and fostering trade to boost growth.
White House Press Secretary Sean Spicer says the deal was not in America's best interest.
"As the President has said many times, this type of multinational agreement is not in our best interest and he's moving quickly to advance trade policies that increase the competitiveness of the American worker and manufacturer. This executive action ushers in a new era of US trade policy in which the Trump administration will pursue bilateral trade opportunities with allies around the globe."
TPP nations had anticipated the move.
Earlier, Japanese Chief Cabinet Secretary Yoshihide Suga said Japan hoped to explain the importance of staying on course with the trade pact as a source of growth and stability.
"We have an agreement with the 12 nations including the United States. Based on these facts, we first hope to promote the understanding of its significance to the United States. We want to take every opportunity to tenaciously appeal to, and seek understanding on, the facts about the TPP and its specific meaning for the United States."
In response to Mr Trump's decision, Mexican President Enrique Pena Nieto says Mexico will immediately seek bilateral deals with other countries in the TPP.
"In trade we reaffirm ourselves as being an open nation to the world which participates in the world market with products and services of high value. With a clear difficulty to materialise the TPP, Mexico will begin immediately with conversation which will generate new trade agreements, bilateral trade agreements, with the participating countries in this treaty."
There are some who are happy the TPP will never be ratified.
Critics argued it was a mechanism in direct competition with China.
There were also concerns the trade pact would mainly benefit wealthy corporations at the expense of workers and the environment.
To take effect, the deal has to be ratified by February 2018 by at least six countries that account for 85 per cent of the group's economic output.
That means Japan and the US have to be on board.
But Mr Trump's comments suggest Congress will be directed to clearly reject it - if they get to vote on it at all.
