Background: Health reform is on the agenda of the recently elected South African president. A National Health Insurance Scheme (NHI), a single-payer and universal health insurance plan, is the foremost option under consideration. This study examines the health and economic gains that South Africa may have at stake in health reform. Method: This descriptive study estimates the avoidable mortality rate in South Africa, or deaths that occur prematurely and could have been prevented with proper treatment for select conditions. The study also estimates the disability-adjusted life years (DALYs) associated with these premature deaths. The study compares the avoidable mortality rate in South Africa with the rates in countries falling into three overlapping groups: (1) countries with similar national health spending as South Africa, (2) countries with similar national health spending and universal health insurance coverage, and (3) countries with similar national health spending, universal health insurance coverage, and single-payer systems. Data: The source of data for avoidable mortality estimates is the World Health Organization (WHO) mortality database reporting the number of registered deaths in 2005. The source of data for the associated DALYs is the Mortality and Burden of Disease Estimate for WHO Member States in 2004. Results: South Africa could potentially gain up to 184,085 lives and reduce the burden of disease by 14.2 million DALYs by avoiding premature deaths under a single-payer system like the NHI. Meeting United Nations Millennium Development Goals could save an additional 32,190 lives. In addition to health reform, a healthy, productive, and skilled workforce is necessary to reach these goals, but the country's skilled-labor unemployment rate is high and its investment in health-professional training is low. Conclusion: Reform could impact health and economic growth via a healthier, productive workforce and demand for quality healthcare.