De Santis, who was instrumental in launching the Opodo brand in the UK, Germany and France, is joining international branding consultancy Twelve Star Communications as chief executive.
His responsibilities at Opodo have been handed to head of marketing development Lorraine Twohill, who becomes Opodo's top marketer.
Opodo, backed by nine major airlines including BA, launched its UK site less than a year ago. It is currently in the middle of an ad blitz by Leagas Delaney and has introduced the tagline "Travel your way" to replace "Your flight on your terms", encouraging customers to book other travel products as well as flights.
Opodo is the leading online travel players in France, but lags lastminute.com in the UK in sales, despite spending £4m on marketing over the past year.
Prior to Opodo, de Santis was chief marketing officer at web currency Beenz.com and acted as an adviser to the EU for the introduction and communication of the Euro.
Twelve Star, which has offices in the UK, US and Spain, counts Pirelli and the European Parliament among its major clients.
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