UKIP is expected to mount a lavish campaign, bankrolled by its campaign director, the millionaire businessman Paul Sykes.
A UKIP spokesman said it would be targeting the Lib Dem's backing for EU fishing quotas, which he claimed had "destroyed" Hartlepool's fishing industry.
Mr Kilroy-Silk, a former BBC chat show host who resigned following comments about Muslims in a newspaper column, said: "This appointment of Mandelson shows that the European Union is a gravy train for failed politicians.
"He has never been the natural person to represent the people of Hartlepool. Now the prime minister has found him something better to do he is off, without a thought for his constituency.
"If I was a constituent I would feel very used and angry and would want to take my revenge on Labour at the by-election."
The party did not field candidates in Leicester South and Birmingham Hodge Hill, as it was "keeping its powder dry" for the expected Hartlepool contest, a spokesman said. Unquote
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