Frenchman Charles Champion is the third official to lose his post after delays in producing the world's largest airliner forced the resignation of the company's chief executive and the co-head of parent EADS during a corporate crisis in July.
The change on Monday coincided with the troubled superjumbo's first test flight involving real passengers – 474 volunteer Airbus staff.
Airbus said Champion had been replaced by Mario Heinen, a 50-year-old executive from Luxembourg.
The move is the first key appointment by Christian Streiff, the Airbus CEO, since he was drafted in from outside the aviation industry to replace Gustav Humbert as the head of Airbus in July.
Champion will serve Streiff as an adviser, Airbus said.
The double-decker A380 is seen as a make-or-break project for Airbus which vies with its only rival Boeing for leadership of the global market for large commercial jets.
Heinen's first task will be to ensure that there is no further slippage in deliveries, with Airbus already facing penalty payments to airlines over previous delays.
The A380, the world's largest airliner, is due to be delivered to its first customer Singapore Airlines by the end of 2006 after two sets of delays totalling a year.
Hundreds of Airbus employees boarded the lower deck of the A380 for the first of four test sorties known as "Early Long Flights" lasting seven to 15 hours on Monday.
Airbus staff in France, Germany, Spain and Britain, competed through lots for a place on the first passenger test flight, which took off from Toulouse in southwest France at 0758 GMT.
Capable of carrying 555 people in standard three-class layout, or over 800 in all-economy, the A380 is billed as the industry's answer to airport congestion and rising air traffic.
But wiring installation problems cost EADS two billion euros in anticipated lost profits and sliced a quarter off its share price in June, plunging the pan-European firm into its worst crisis since it was founded in 2000.
Boeing has a competing strategy based on mid-sized long-haul jets capable of carrying passengers to their final destination, rather than large regional hubs to be served by the A380.
Airbus is working on a rival aircraft, the A350, to catch up with buoyant sales of the mid-sized Boeing 787 Dreamliner.