Ms. Mlambo-Ngcuka drew applause from fellow Cabinet members as she took the oath of office at a ceremony Thursday in Cape Town.
The former minerals and energy minister said fighting the AIDS pandemic and improving the economy would be priorities in her new post
Ms. Mlambo-Ngcuka replaces Jacob Zuma who was fired last week by President Thabo Mbeki after he was implicated in a bribery scandal.
South Africa's National Prosecuting Authority says they are bringing corruption charges against the former deputy president. Earlier this month, Mr. Zuma's financial adviser was sentenced to 15 years in prison for bribing him.
Some information for this story provided by AFP and AP.