Although cystatin C and creatinine are established markers of kidney function, non-renal factors can differently affect circulating levels of each marker. Cystatin C levels are more likely to be increased when high blood pressure and inflammation are present, which are well-known cardiovascular risk factors. Here, we aimed to evaluate whether the difference in eGFR between creatinine- and cystatin C- based equations could be used to predict adverse cardiovascular outcome in patients with chronic kidney disease (CKD). Using a database from the KoreaN cohort study for Outcome in patients with CKD (KNOW-CKD), we studied 2018 patients with CKD stage 1 to 5 prior to dialysis. The eGFR difference (eGFRdiff) was calculated by subtracting cystatin C-based eGFR (eGFRcys) from creatinine-based eGFR (eGFRcr). Coronary arterial calcification score (CACS) was measured by computed tomography. The primary outcome was the occurrence of fatal and non-fatal cardiovascular events. The mean eGFRdiff was 0.5±11.1 mL/min/1.73m2, and the difference was higher in advanced CKD stages (P for trend < 0.001). When patients were categorized into eGFRdiff tertiles, patients in the middle and highest tertiles had significantly higher blood pressure, C-reactive protein levels, and CACS than those in the lowest tertile (P for trend <0.001). The highest eGFRdiff tertile was associated with significantly higher risk of cardiovascular outcome (hazard ratio, 2.18; 95% confidence interval [CI], 1.30-3.68; P = 0.003) as compared to the lowest tertile. This relationship was persistent after further adjustment of eGFRcr, eGFRcys, or eGFRcr-cystatin C. In subgroup of 978 patients who measured follow-up CACS at year 4, eGFRdiff was significantly associated with accelerated CAC progression (≥ 50/year) (odds ratio, 1.04; 95% CI, 1.01-1.06; P = 0.006). A greater difference between eGFRcr and eGFRcys was associated with higher risk of adverse cardiovascular outcome and faster CAC progression in patients with CKD.