The agency will responsible for the hotel site's social media strategy, from strategic advice and in-house training, to managing presences on Facebook and Twitter.
Activity will initially launch across France, Italy, UK and Sweden, before moving to the rest of Europe next year.
Matthew Walls, EMEA marketing director at Hotels.com said: "We Are Social came up with a plan that showed it really knew how to handle social media at scale – helped hugely by its international presence – and instilled a lot of confidence internally with its proposals for training and staff development."
Robin Grant, We Are Social's managing director, said: "With the web as the first port of call for people looking to book holidays, Hotels.com understands the value of ensuring its social media strategies are strong enough to support its business objectives of increased brand awareness, reaching new customers and ultimately increasing sales."
In March, Hotels.com launched its latest TV ad to target hotel "obsessives". The animated ad, created by brand consultancy Lambie Nairn, retained the "Wake Up Happy" endline, and introduced a new brand character to demonstrate the website's "obsession" with hotels.