The head of brand and marketing communications will leave the airline's marketing department in the charge of Tiffany Hall, head of marketing and distribution.
O'Brien will leave BA at the end of March upon which she will join office services firm Regus in the newly created role of global chief marketing officer.
News of O'Brien's departure follows the resignation of Martin George, BA's commercial director, who left in October in the wake of alleged price-fixing on long-haul flights.
O'Brien joined BA in 1989 as product manager on long-haul flights. She has gradually worked her way up the BA corporate ladder, leading to her promotion in February last year from head of marketing for the UK and Ireland to her latest role.
George's resignation was accompanied with a statement making it clear that while inappropriate conversations about long-haul fuel surcharges had been taken place, he was not directly involved in them.
BA said it would seek a direct replacment for O'Brien.
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