The site between Rathbone Place and Newman Street is currently owned by the Royal Mail.
Great Portland will lease the current site back to Royal Mail until June 2013 before starting on plans for major mixed-use redevelopment.
Great Portland chief executive Toby Courtauld Chief Executive said: “We are delighted to have added this important West End site to our medium term development pipeline.
“Its redevelopment will accelerate the regeneration of the East End of Oxford Street, one of London’s most exciting submarkets, which is set to benefit significantly from the opening of Crossrail.
“We look forward to working closely with both Royal Mail Group and Westminster City Council to maximise the benefit the site can bring to this part of the Capital.”