South Africans will be voting in provincial and national polls. A new parliament will choose a new president.
The elderly and infirm have already begun to cast their ballots in the vote to elect candidates for the 400-seat National Assembly.
The ANC faces its toughest challenge ever from the Congress of the People (Cope), a new opposition party created by former senior members of the ANC.
The ruling party's two-thirds majority could also be reduced by the Democratic Alliance (DA), an opposition party which hopes to capitalise on growing frustrations with poverty, crime and Aids.
Al Jazeera's Haru Mutasa, reporting from Cape Town, where charities started giving out anti retroviral drugs eight years ago, said that while less stigma is now being attached to those with HIV/Aids, more people are being infected.
According to the Treatment Action Campaign, at least 800 people in South Africa die of Aids every day.
Five million people are known to be infected with the virus.
Alex Matthew, a political blogger in Cape Town, capital of the Western Cape province where the DA is popular, told Al Jazeera "there just hasn't been service delivery [by the ANC] required to put people out of poverty".
"Housing is a huge problem. We have literally thousands and thousands of people coming from the Western Cape into Cape Town to find jobs, and there are no houses for them. Ther has been tremendous dis-satisfaction," he said.
High turnout predicted
Zuma, a former deputy president, is expected to become the new president as the ANC remains the dominant political force.
The party last weekend held a mass rally in Johannesburg which was boosted by a surprise appearance by Nelson Mandela, the country's first black president, whose attendance was seen as a major endorsement.
Zuma has been facing corruption charges which were dropped by the National Prosecuting Authority (NPA) on a technicality.
The Independent Electoral Commission (IEC) expects a high turnout, with more than 20 million people expected to cast ballots, said Kate Bapela, an IEC spokeswoman.
"All of our 19,726 stations will be open at 7am on Wednesday. At this stage we do not foresee any disruptions or hiccups," she told AFP news agency.
In total, 26 parties are competing but the vast majority will be taking part only in provincial elections.