Roland Absalom, who took up the headship of Fullhurst College in Leicester in May, has left citing "personal and private reasons". When he started the job he pledged to stay until at least September 2010.
The catalogue of resignations at Fullhurst started in January when headteacher Michael McPherson resigned after the school was put in special measures.
He was followed by Jill Hislop, the then executive principal, who resigned two months later after a row with teaching unions, which claimed working conditions at the school were "intolerable".
Mr Absalom was appointed by David Kershaw, the school's new executive principal, who is credited with turning around New College, Leicester, once branded one of the worst schools in the country.
Mr Kershaw will now be assisted by Carolyn Robson, head of Rushey Mead, who will work part of her week at Fullhurst until a permanent appointment can be made. The two schools may enter into a partnership.
The problems at the school follow a warning from Schools Secretary Ed Balls that exam results in Leicester are too low.
He has ordered an inquiry into National Challenge schools - those where fewer than 30 per cent of pupils get five good GCSEs, including English and maths - to be carried out by former chief inspector of schools Mike Tomlinson