Background Myeloperoxidase (MPO) catalyzes the formation of reactive nitrogen species and levels are elevated in patients with chronic kidney disease (CKD). Although increased oxidative stress and inflammation are associated with progression of CKD and cardiovascular disease (CVD), relationships between MPO concentration, CKD progression, CVD, and death remain unclear. Study Design Prospective cohort. Setting & Participants 3,872 participants from the Chronic Renal Insufficiency Cohort (CRIC) who had MPO measured at baseline. Exposure Baseline MPO concentration. Outcomes CKD progression (kidney transplantation, dialysis initiation, or 50% decline in baseline estimated glomerular filtration rate [eGFR] and eGFR ? 15 mL/min/1.73 m2), CVD (heart failure, myocardial infarction, or stroke), and death. Analytical Approach Cox proportional hazards models. Results In adjusted analyses, higher MPO level (per 1-SD increase in log-transformed MPO) was associated with 10% higher risk for CKD progression (adjusted HR, 1.10; 95% CI, 1.01-1.19; P = 0.03), 12% higher risk for CVD (adjusted HR, 1.12; 95% CI, 1.03-1.22; P < 0.01), and 13% increased risk for death (adjusted HR, 1.13; 95% CI, 1.04-1.22; P < 0.01). There was evidence for effect modification of the association of MPO level with CKD progression by baseline eGFR (P interaction = 0.02), but not for CVD (P interaction = 0.2) or death (P interaction = 0.1). In stratified analyses, MPO level (per 1-SD increase in log-transformed MPO) was associated with greater risk for CKD progression among participants with eGFR > 45 mL/min/1.73 m2 (adjusted HR, 1.23; 95% CI, 1.03-1.46; P = 0.02) compared with those with eGFR ? 45 mL/min/1.73 m2 (adjusted HR, 1.10; 95% CI, 1.02-1.20; P = 0.02). The association of MPO level with CVD and death was no longer significant after adjustment for cardiac biomarkers. Limitations Potential residual confounding, lack of repeated measurements of MPO. Conclusions Higher MPO level was associated with increased risk for CKD progression, but not with CVD and death in patients with CKD from CRIC. Whether therapies aimed at reducing MPO activity can result in improved clinical outcomes is yet to be determined.