Isobel, which has handled the £10 million creative account for the past two years, was also appointed to the business in the short term in 2004.
The account was previously held by TBWA\London and was run by Andrew McGuinness before he was promoted to managing director of TBWA.
Isobel will not make any redundancies following the account's departure. The Isobel managing partner, Paul Houlding, said: "We are extremely proud of the work that we've done for npower over the past two years, but it's time we moved on to concentrate on other clients and new-business opportunities."
Last year, npower's owner, the German energy giant RWE, announced its intention to double its marketing spend to £20 million.
Last week, npower handed its £3 million online account to Grand Union.
Npower could not be reached. BMB declined to comment.