Background: Ongoing quantification of trends in high blood pressure and the consequent disease impact are crucial for monitoring and decision-making. This is particularly relevant in South Africa (SA) where hypertension is well-established. Objective: To quantify the burden of disease related to high systolic blood pressure (SBP) in SA for 2000, 2006 and 2012, and describe age, sex and population group differences. Methods: Using a comparative risk assessment methodology, the disease burden attributable to raised SBP was estimated according to age, se, and population group for adults aged =25 years in SA in the years 2000, 2006 and 2012. We conducted a meta-regression on data from nine national surveys (N=124 350) to estimate the mean and standard deviation of SBP for the selected years (1998 - 2017). Population attributable fractions were calculated from the estimated SBP distribution and relative risk, corrected for regression dilution bias for selected health outcomes associated with a raised SBP, above a theoretical minimum of 110 - 115 mmHg. The attributable burden was calculated based on the estimated total number of deaths and disability-adjusted life years (DALYs). Results: Mean SBP (mmHg) between 2000 and 2012 showed a slight increase for adults aged =25 years (127.3 - 128.3 for men; 124.5 - 125.2 for women), with a more noticeable increase in the prevalence of hypertension (31% - 39% in men; 34% - 40% in women). In both men and women, age-standardised rates (ASRs) for deaths and DALYs associated with raised SBP increased between 2000 and 2006 and then decreased in 2012. In 2000 and 2012, for men, the death ASR (339/100 000 v. 334/100 000) and DALYs (5 542/100 000 v. 5 423/100 000) were similar, whereas for women the death ASR decreased (318/100 000 v. 277/100 000) as did age-standardised DALYs (5 405/100 000 v. 4 778/100 000). In 2012, high SBP caused an estimated 62 314 deaths (95% uncertainty interval 62 519 - 63 608), accounting for 12.4% of all deaths. Stroke (haemorrhagic and ischaemic), hypertensive heart disease and ischaemic heart disease accounted for >80% of the disease burden attributable to raised SBP over the period. Conclusion: From 2000 to 2012, a stable mean SBP was found despite an increase in hypertension prevalence, ascribed to an improvement in the treatment of hypertension. Nevertheless, the high mortality burden attributable to high SBP underscores the need for improved care for hypertension and cardiovascular diseases, particularly stroke, to prevent morbidity and mortality.