The combined airline will employ about 75,000 staff
Delta Air Lines has completed a $2.8bn(£1.7bn) deal to take over US rival Northwest Airlines.
It came after the Justice Department granted antitrust approval and said the deal could produce efficiencies that "would benefit US consumers".
The new airline, to be called Delta, will have annual revenue of more than $35bn and employ about 75,000 staff.
It will serve customers in 66 countries and more than 375 cities - "more than any other airline", it is claimed.
Delta Air Lines was the US's third-largest airline, and Northwest was fifth biggest. The combined company will be based in Atlanta.
"The airline industry faces a very difficult economic environment around the world and this merger gives Delta increased flexibility to adapt to the economic challenges ahead," said Delta chief executive Richard Anderson.
An unspecified number of job cuts are expected to reduce overlap in corporate and administrative departments.
The merger comes amid consolidation in the aviation sector as airlines struggle to survive amid high fuel prices and economic turmoil.
Delta says its "strong liquidity balance" will help it cope with the challenges of the weakening global economy.