Three quarters of the country's 27.4 million eligible voters have registered to vote and a high turnout is expected, showing the poll is being taken as seriously by South Africa's black majority as when apartheid ended 10 years ago.
The former liberation movement hopes to win power in the only two provinces it does not already control and grab a two thirds majority in parliament, enough to change the constitution.
This is seen as a likely outcome despite the festering problems of widespread poverty, a 40% jobless rate, and AIDS - which affects an estimated one in nine South Africans.
"The ANC has historical and political capital which other parties lack ... and failures can still be blamed on the legacy of apartheid," Vista University analyst Sipho Seepe told Reuters.
"These enhance ANC popularity because the party has a track record of fighting for the people and they can say 'the struggle must continue'. They may get up to 68% of the vote."
In contrast to South Africa's first democratic election in 1994, campaigning has been largely peaceful - despite sporadic violence in the Zulu heartland of KwaZulu-Natal, which the ANC has vowed to wrest from the opposition Inkatha Freedom Party.
Only a handful of people have died in politically-motivated killings in the province this year, compared to scores in the last poll in 1999 and an estimated 20,000 in 1994.
But IFP spokesman Musa Zondi said late on Tuesday one of his party's leaders was attacked by gunfire from an AK47 as he drove his car through the KwaZulu-Natal coast city of Port Shepstone.
There was no immediate comment from the ANC, which has repeatedly vowed to ensure that the election is free and fair.
"The state organs are positioned to act against anybody who tries to disrupt the process," President Thabo Mbeki said on Tuesday.
Hundreds of rifle-toting soldiers and thousands of policemen were sent out in force to patrol the province.
KwaZulu-Natal provincial election officer Mawethu Mosery dismissed threats by IFP leader Mangosuthu Buthelezi to reject election results from the province if the polls were rigged.
"In my mind, there isn't any opportunity for anyone to manipulate the elections. The electoral commission works independently and is impartial and there is no legitimate reason to express doubts about these issues," he told Reuters in Durban.