MediaCom will initially work on a project basis for Opodo after winning the account in a pitch.
The previous incumbent on the business was Carat, which declined to repitch for the account.
Leagas Delaney, which handles pan-European creative for Opodo, is unaffected by the appointment of MediaCom.
There have been significant changes in Opodo's marketing team this year.
Nicholas De Santis, its marketing director, left in February to join a business consultancy.
Opodo then appointed the former ITV Digital customer service and operations director Karen Richardson as the commercial director and Richard Hadfield, a Thomas Cook marketer, as its UK country manager.
The travel portal launched its UK services in 2002 with a large press campaign through Leagas Delaney. The agency then created a TV campaign backed by the Iggy Pop track Lust for Life. It used the line: "Your flights on your terms ... and about time too."
Opodo launched in 2001 as a European joint venture between nine airlines including British Airways, KLM and Lufthansa. The company offers flights, hotels, packages and insurance.
MediaCom was unavailable for comment.