Up to 900 full-time posts are set to be axed at a city council less than two years after 2,000 jobs were cut.
Manchester City Council said it planned to open a voluntary severance scheme for staff ahead of expected spending reductions to be announced by the Government next month.
Council chiefs are predicting its funding will be reduced by about £80 million over the next two years.
The leader of the council, Sir Richard Leese, said: "This is a very difficult time for Manchester City Council staff and, indeed, Manchester residents. We have already seen our staff levels reduced by more than 2,000 over the past two years after the Government-imposed £109 million of cuts last year, rising to £170 million this year.
"It's important to stress that we don't have the details of our financial settlement yet but our best estimate is that it could impose another £80 million of cuts. This is going to put even more pressure on our services - and on staff who are doing a great job delivering those services - and will mean that we will have to radically rethink how we provide for Manchester people.
"Staffing costs are a significant proportion of expenditure and we believe that the necessary reduction could be in the region of 700 to 900 posts. As a result we are introducing voluntary early retirement and severance schemes, although no applications will be approved until after we have received our settlement from Government and on that basis have set a budget. The council remains committed to aiming to avoid compulsory redundancies.
"Despite this news, we remain committed to ensuring we protect and support Manchester's most vulnerable people, while delivering our essential services efficiently and effectively and doing all we can to attract jobs and investment to the city and continue to grow our economy."
The council said this year's £170 million spending reduction was one of the five worst settlements in the country.
A spokesman for the Department for Communities and Local Government said: "No decisions have yet been made on the details of future years' funding, ahead of the Autumn Statement and Local Government Finance Settlement.
"Councils account for a quarter of all public spending - this year English councils will spend £114 billion - so it is vital they continue to play their part tackling the inherited budget deficit by making sensible savings through better procurement, greater transparency and sharing back offices."