Leadership Academy for Girls
The academy aims at giving 152 girls from deprived backgrounds a quality education in a country where schools are struggling to overcome the legacy of apartheid.
Former South African president Nelson Mandela, present for the opening celebration, praised Winfrey.
"This is not a distant donation you've made but a project that is clearly close to your heart," Mandela said.
"If you are surrounded by beautiful things and wonderful teachers who inspire you, that beauty brings out the beauty in you"
"South Africa should take a lesson from you about what personal commitment means."
Singers Mariah Carey, Tina Turner and Mary J. Blige, comedian Chris Rock, actor Sydney Poitier and filmmaker Spike Lee attended the star-studded school launch.
"Girls who are educated are less likely to get HIV/AIDS and in this country which has such a pandemic, we have to begin to change the pandemic," she said.
Many of the girls come from families affected by the disease which has infected 5.4 million of the 48 million population and hit women disproportionately hard.
"I was a poor girl who grew up with my grandmother, like so many of these girls, with no water and electricity," said the talk show host.
The idea for the school was born in 2000 at a meeting between Oprah Winfrey and anti-apartheid icon Mandela.
She said she decided to build the academy in South Africa rather than the United States out of love and respect for Mandela and because of her own African roots.
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Built on 52 acres, the 28-building campus, which was originally to cost $10 million, and not the actual $40 million, boasts modern classrooms, computer and science laboratories, a library, theatre and health centre.
Each girl has a two-bedroom suite, but Winfrey rejected suggestions that her school was elitist and unnecessarily luxurious.
"If you are surrounded by beautiful things and wonderful teachers who inspire you, that beauty brings out the beauty in you," she said.
The result was a far cry from the state-funded schools, plagued by gang violence, drugs and a high rate of pregnancy among school girls.
Despite government efforts to improve the school system, the education department said last week that two-thirds of the 1.6 million children who started school 12 years ago has dropped out.
Only five per cent of the total intake did well enough in their studies to be eligible to go to university.
"I went to their homes. I met their teachers and their parents. I know all of them by name," Winfrey said.
"Their story is my story."