BACKGROUND: South Africa has the greatest burden of HIV-infection in the world with about 5.2 million HIV-infected adults. In 2003, the South African Government launched a comprehensive HIV and AIDS care treatment program supported by the United States in 2004 through the President's Emergency Plan for AIDS Relief (PEPFAR). METHODS: To describe the scale-up and continuation of antiretroviral therapy in South African Government and PEPFAR-supported sites in South Africa, we conducted a retrospective analysis of routinely collected program reporting data, 2005-2009. RESULTS: From 2005 through 2009, the average rate of persons initiated on antiretroviral therapy in PEPFAR-supported South African Government treatment programs increased nearly four-fold from 6,327 a month in 2005-2006 to 24,622 a month in 2008-2009 resulting in an increase from 33,543 patients on continued treatment in April-June 2005 to 631,985 patients in July-September 2009. Of those 631,985 patients receiving treatment, 65% were women. Men were more likely to be lost to follow-up (9.2% vs. 7.8%, PR 1.18, 95% CI 1.17-1.19) and more likely to die (5.6% vs. 4.1%, PR 1.36, 95% CI 1.35-1.37) than women. CONCLUSIONS: Scale-up and continuation of antiretroviral therapy in South Africa has been a remarkable medical accomplishment. Because more women receive and continue treatment, more efforts are needed to treat and retain men.