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Background LDL-C is a key contributor to cardiovascular disease (CVD), but the exact attributable disease risk in South Africa is not known. This study aimed to quantify the burden of disease attributable to LDL-C in South Africa for 2000, 2006 and 2012. Methods National mean LDL-C estimates were derived from 14 observational studies using a meta-regression model. LDL-C estimates together with relative risks from the Global Burden of Disease Study 2017 were used to calculate a potential impact fraction (PIF) and applied to IHD and ischaemic stroke estimates to calculate attributable deaths and disability-adjusted life years (DALYs). Uncertainty analysis was performed using Monte Carlo simulation. Results LDL-C declined between 2000 and 2012 in males (2.74 mmol/L to 2.58 mmol) and females (3.05 mmol/L to 2.91 mmol/L). Attributable DALYs increased between 2000 (N = 286 712) and 2006 (N = 315 125) but decreased thereafter in 2012 (N = 270 829). Attributable age-standardised death rates declined between 2000 and 2012 in males (98 per 100 000 to 78 per 100 000) and females (81 per 100 000 to 58 per 100 000). Conclusions The decreasing trend in the age-standardised attributable burden due to LDL-C can be lowered further with the introduction of additional population-based CVD prevention strategies. Key messages This study highlights that high LDL-C in South Africa is responsible for a large proportion of the emerging CVD and should be targeted by health planners to reduce disease burden. [ABSTRACT FROM AUTHOR]