"We confirm that there has been an accident with an A400M in Sevilla," Airbus Defence and Space said in a statement.
"Airbus is devastated to confirm that of a total crew of six on board we have lost four of our crew members in the accident," the company said. "Two other crew members are currently in hospital in a serious condition".
All the crew members are Airbus employees and are Spanish, the company said.
"We express our deepest sympathy. They were fellow countrymen," said Spanish Prime Minister Mariano Rajoy, Reuters reported.
"The crisis room is open," Airbus said. The aircraft is MSN023, built for Turkey.
Picture shows wreckage of an Airbus A400M military transport plane after crashing near Sevilla on May 9, 2015. An Airbus A400M military transport plane crashed near Seville in southern Spain on Saturday while apparently on a test flight, officials said.
Photo Credit: CRISTINA QUICLER/AFP/Getty Images
Television channel Telecinco carried footage of dense black smoke rising from the crash as filmed by a passing car, and there was video showing fire engines and other emergency vehicles at the wreckage.
Airbus is sending a "go-team" of company experts to the scene and is cooperating with the authorities, the company said.
Turkey signed in 2003 an order for 10 A400Ms, with the last of the units due to be delivered in 2018. Turkey has previously complained about a late delivery of the Airbus aircraft and expected to claim penalties.
Airbus handed over the first two aircraft for Turkey last year and a further two were due this year.
Airbus Military has an assembly and test site for transport aircraft here.
Belgium, France, Germany, Luxembourg, Malaysia, Spain and Britain have also ordered the A400M. The orders total 174 of the units and 12 delivered and operating, said the Airbus website. The company has dubbed the plane the Grizzly.