The agency saw off competition from HHCL/Red Cell and Lowe to win the business after the incumbent, Leagas Delaney, declined to repitch.
Opodo is understood to be looking for a change of direction to help it stand out in an increasingly competitive market. Karmarama has been briefed to deliver an integrated brand campaign, aimed at raising awareness.
The ads are expected to break sometime over the next two months and will incorporate press, poster, radio and online elements.
The review was overseen by Opodo's UK country manager, Neil Mott, who recently joined from easyJet, where he was the marketing manager for the UK.
The travel portal launched in 2001 as a joint venture between nine European airlines, including British Airways, KLM and Lufthansa, offering a one-stop shop for flights, packages and insurance.
It first promoted its UK services in 2002 through a press and TV campaign by Leagas Delaney.
The TV execution used the Iggy Pop track Lust for Life. It incorporated the endline: "Your flights on your terms ... and about time too."
Opodo operates in France, the UK and Germany, but is understood to be planning further expansion in Europe this year.
Leagas Delaney will continue to hold the account in Germany.
Media planning and buying were not affected by the review. MediaCom, which was appointed to the account, worth £5 million, in September, will continue to handle media.
Karmarama was recently appointed to create a campaign for Amnesty International.