The campaign, created by design agency Sedley Place, allows consumers to tweet their Christmas messages to the Twitter account, @cokezone, to be displayed on the Coke-owned ad sign.
Tweeters need to follow @cokezone and tweet a message for the Piccadilly site to the account.
People who have their tweets displayed will receive a direct message from Coca-Cola's account and their message will be shown on the sign five minutes later.
Tweets can also be viewed live on the brand’s engagement site, www.cokezone.co.uk/Piccadilly, via a webcam set up to film the sign.
Zoe Howorth, market activation director, Coca-Cola GB, said: "The Piccadilly sign provides Coca-Cola with a unique interactive platform and we're delighted that consumers can use it to spread their Christmas messages this year.
"This activation puts our fans at the heart of the activity, allowing them to engage and communicate with people everywhere."
The campaign runs until 23 December.