American Express said its president, Ed Gilligan, died after becoming ill on a flight to New York.
Mr Gilligan started his career at the company as an intern 35 years ago and became vice chairman in 2007 and president in 2013, it said in a statement.
The company did not describe the nature of his illness.
American Express chief executive Ken Chenault said Mr Gilligan’s death was “devastating news” in a statement.
The company said he is survived by his wife Lisa, and their four children.
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