Background Elevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long‐term or is independent of renal function and other important biomarkers. Methods and Results Cystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow‐up, 6 years) and long‐term (median follow‐up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR‐creatinine, then GFR‐creatinine‐cystatin C). Over 6 years, in fully adjusted multivariable time‐to‐event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07–1.74; P =0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19–1.82; P <0.001). Over 16 years, the association of baseline cystatin C with coronary heart disease, cardiovascular, and all‐cause mortality persisted (each P <0.001) and remained significant after adjustment for estimated GFR‐creatinine‐cystatin C. Cystatin C also predicted the development of chronic kidney disease for 6 years (odds ratio, 6.61; 95% CI, 4.28–10.20) independently of estimated GFR‐creatinine and other risk factors. However, this association was no longer significant after adjustment for estimated GFR‐creatinine‐cystatin C. Conclusions Cystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all‐cause mortality. Prediction of long‐term mortality was independent of improved estimation of GFR. Registration URL: https://anzctr.org.au ; Unique identifier: ACTRN12616000535471.