Several senior government officials, including the head of the border service, were arrested after police raids on dozens of premises Thursday, including the interior and environment ministries and offices linked to the justice ministry.
Macedo, 55, who had been in the job since 2011, said yesterday he "had no personal responsibility" in the case but his "political authority" had been weakened by the scandal.
In televised comments, he said he had quit to "defend the government and the authority of the state and the credibility of its institutions."
Among those held were Manuel Jarmela Palos, the head of the frontier police agency SEF, Maria Antonia Anes, the secretary general of the justice ministry, and Antonio Figueiredo, the head of the Institute of Registries and Notaries.
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While Macedo has not been targeted in the probe, he has close ties to Figueiredo, Portuguese weekly Expresso said yesterday.
Portugal launched the "golden visa" scheme in 2012 while grappling with a debt crisis.
Under the scheme, foreign investors buying property worth 500,000 euros (USD 623,000) or more and keeping it for at least five years received residency rights in Portugal and more importantly, visa-free travel throughout the European Union's Schengen zone.
The other options offered to get residency rights in Portugal include transferring at least one million euros into the country or creating at least 10 new jobs there.
Once the residency rights have been granted, the beneficiaries are only required to spend seven days in a year in Portugal.