Labour won the Wythenshawe and Sale East parliamentary by-election today while the Conservatives were pushed into third place by Ukip and Lib Dem support was decimated.
Former councillor Mike Kane held the seat for the party, polling 13,261 votes.
Ukip surged from fifth place in 2010 to second despite leader Nigel Farage complaining the campaign had been "as dirty as they come".
The party's success and the demise of the Tory vote is yet another by-election blow to Prime Minister David Cameron.
But the Liberal Democrats were dealt a humiliating blow when they polled just 1,176 votes - not enough to hold their deposit.
The by-election was brought about by the sudden death of the serving MP, Paul Goggins, on January 7, at 60.
In his victory speech, Mr Kane said voters had "sent a very clear message" to the Government.
" They have rejected the failed policies of the out-of-touch Tories, t hey have rejected the isolationism and scaremongering of Ukip.
"It's a result which emphatically demonstrates that people here know the NHS is not safe in David Cameron's hands, and that we've had enough of his utterly out-of-touch government."
Labour increased its share of the vote by 11% while Ukip's share rocketed by 14%.
Ukip candidate John Bickley said he was "over the moon" with the result and claimed his party was "in better shape" than the Conservatives.
He told Sky News: "We've taken votes off all of them and that includes Labour."
The figures make gloomy reading for the Liberal Democrats, with vote share plummeting by 17% to take them below the crucial 5% needed to hold their deposit.
Some 24,024 votes were cast - a turnout of 28.24%.
It is the latest in a number of by-elections that has seen Ukip take second place, including South Shields and Eastleigh last year.
Mr Farage, speaking from the count at Manchester Central convention centre, said he was pleased with how his party performed but complained forcefully about the way the election was run.
He said the fact that postal votes were issued just three days after the election was declared, allowing people then to cast votes, reduced the poll to a farce - and he joked he had "been on benders" longer than election campaigns that long.
He said: "This is nothing to do with this result, this is a point I have made at every single by-election and I'm going to go on making it, it's just at Wythenshawe it reached farcical proportions.
"Nominations for candidacy closed on the 29th of January, first postal votes arrived on the 1st of February, that's a three day campaign.
"And it doesn't matter how people voted but the point about democracy is you should see who the candidates are, see what their agendas are and then form an opinion.
"That is not happening and it is reducing, frankly, these by-elections to farces.
"It is a system that allows the incumbent party to call the by-election at a time of their choosing and it doesn't give a free, open contest to anybody else.
"We are a party that is all about British democracy, we want sovereignty to come back to this country but we also want free, proper open elections and what the postal system has done, not what it intended to, it has reduced by-elections frankly to farces where half the votes weren't decided today on February 13th they were decided a fortnight ago. I'm a reformer."
On the performance of his party Mr Farage declared himself "very pleased".
He added: "It represents really good solid, steady progress, not an easy constituency for us, we have got no history here.
"When you start from a base of nothing and your level of public recognition is very low then to do what we have done in a very short space of time, no delighted, anything over 15% was what I was hoping for and had it been over 20%, it would have been a terrific result for us so 18%, no I'm very pleased."