Pakistan's Supreme Court has upheld bans on former prime minister and opposition leader Nawaz Sharif and his brother, Shahbaz, from elected office.
Nawaz Sharif's PML-N party holds power in Punjab province. His brother is chief minister but must now step down.
Last June, the high court in the city of Lahore upheld an earlier ruling that barred Nawaz Sharif from running in a parliamentary by-election.
The court said he was ineligible to stand because of a 1999 conviction.
The BBC's Barbara Plett in Islamabad says that the court order will deepen the rift between the Sharifs and the federal government and increase the chances of political instability in the country.
One of the Sharif lawyers, Akram Sheikh, confirmed that their appeal in the Supreme Court against the earlier ruling had been dismissed.
He said: "[President] Asif Ali Zardari had a hand in the disqualification of Nawaz Sharif and today's decision is also according to his wishes."
President Zardari had a hand in the decision, Nawaz Sharif believes
Nawaz Sharif is not an MP at the moment, but analysts say the court order will force Shahbaz Sharif to step down from the post of Punjab's chief minister.
Nawaz Sharif had been convicted in connection with the 1999 hijacking of a plane carrying then army chief Gen Pervez Musharraf.
The event led to Gen Musharraf ousting Mr Sharif in a coup and going on to become president.
Nawaz Sharif had returned from exile, hoping his ban from office would be lifted by a democratically elected government.
The PML-N and Pakistan's ruling party PPP then emerged as the two biggest parties after last year's elections, trouncing allies of Pervez Musharraf.
They formed a fragile coalition and managed to force Mr Musharraf out of office.
But soon after, Mr Sharif fell out with the PPP leader, Mr Zardari, and they split over the issue of the reinstatement of judges sacked by Mr Musharraf.
Anticipating Wednesday's court's decision, Mr Sharif at the weekend blamed Mr Zardari for deliberately trying to undercut him.
Our correspondent says this raises fears of a return to the bitter political infighting that characterised elected governments in the 1990s, now though, at a time when Pakistan is facing security and economic crises.