Her body was discovered by her brother Moemise Motsepe around 11am at her home in Randburg, the family said in a statement.
She was declared dead at 1pm by paramedics. She died of natural causes.
READ MORE: Lesego Motsepe memorial on Thursday
Motsepe will be remembered for her role as Letti Matabane in the South African soapie, Isidingo. She was part of the cast from 1998 to 2008.
She announced her HIV-positive status on World Aids day in 2011 and became an Aids ambassador.
“She had been living with the disease since 1998,” her family said.
“Since the public announcement that touched many hearts of South Africans, Lesego conducted several workshops and talks on the importance of living with hope when affected by HIV/Aids, directly or otherwise.”
Motsepe is survived by her mother Ivy Skhosana, brothers Moemise and Andile Skhosana, and nieces and nephews.