The 10-member Association of South East Asian Nations (Asean) and Susan Schwab, the US trade representative, signed the Trade and Investment Framework Agreement (Tifa) in Malaysia on Friday.
Under the agreement, the US and Asean are to establish a formal ministerial dialogue aimed at expanding trade and investment.
They have also agreed to initiate a work plan on three projects key to starting free-trade negotiations: The creation of a single-window facility to smooth the flow of goods to the United States, establishing an agreement on sanitary standards to foster agricultural trade, and harmonising standards for pharmaceutical registration and approvals.
"The can-do spirit of the members of Asean reflects the can-do spirit we are so proud of in the United States," Schwab said after signing the pact.
"The Tifa with Asean represents an important step forward in the trade relationship with the region."
The United States is the biggest buyer of Asean goods and the region's largest foreign direct investor, spending $8.7 billion in the region last year, according to Asean data.
Asean is the fourth largest trading partner with the US, Schwab said.
But Washington has played down the prospect of free-trade deals, even though it already has a free-trade pact with Singapore and is in free-trade talks with Malaysia and Thailand - all members of Asean.
Rafidah Aziz, the Malaysian trade minister, said the document was not legally binding but "a framework for technical co-operation".
Both Schwab and Asean ministers have been reluctant to say when free trade negotiations could begin, but one Asean official said that talks could begin in 2010 when six Asean members implement trade liberalisation programmes.
An Asean official said the situation had changed since 2002 when work began at a painstaking pace on the deal.
"Talks took four years to conclude. It began in 2002 but US interest was not there [then]," he said.
"Now they realise the importance of Asean. They want to keep their influence in the region here," he said. "They are aware that trade between Asean and China is increasing."
Asean also includes Brunei, Cambodia, Indonesia, Laos, Myanmar, the Philippines and Vietnam.