Ed Miliband has claimed that Middle England was turning its back on David Cameron after Labour won the Corby by-election on a 12.7% swing.
Andy Sawford's victory by a margin of almost 7,800 votes was the highpoint for Labour in a day of results which was otherwise dominated by the poor turnout in elections to the newly-created post of Police and Crime Commissioner (PCC) across England and Wales.
Conservatives sought to portray their first loss of a Westminster seat to Labour in a by-election for 15 years as a case of "mid-term blues", and cast some of the blame on former MP Louise Mensch for resigning to be with her family in the United States.
Mr Cameron said: "It's a classic mid-term result and obviously made difficult by the fact that the Conservative MP left the seat in question."
Mrs Mensch tweeted: "Very respectable result indeed for whole Tory team against local anger at my resignation for family. & 20 LibDem marginals on target list."
Tory sources suggested that Labour needed to match the 17% swing they achieved in Crewe in 2008 at Corby to be on track for victory in the 2015 general election.
But a jubilant Labour leader told supporters in the Northamptonshire seat: "This constituency is at the heart of our country and this constituency has sent a very clear message today.
"It sent a message that it is putting its trust in a One Nation Labour Party."
Mr Miliband added: "Middle England is turning away from David Cameron and the Conservatives because Middle England feels let down by David Cameron and the Conservatives."
Elsewhere, there were mixed results for Mr Miliband's party, which won Westminster by-elections in the safe seats of Cardiff South and Manchester Central, but was beaten in the race for Bristol mayor by independent George Ferguson and saw Lord Prescott beaten in the Humberside PCC race by Tory local councillor Matthew Grove, who overtook the former deputy prime minister when second preference votes were added up.