Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease (CVD). However, traditional lipid risk factors, including low HDL levels, cannot completely explain the increased risk. Altered HDL proteome is linked with both CVD and CKD, but the role of HDL proteins in incident CVD events in CKD is unknown. In this prospective case-control study, we used targeted proteomics to quantify 31 proteins in HDL from 92 subjects (46 incident new CVD and 46 one-to-one matched controls) at various stages of CKD. We tested associations of HDL proteins with incident CVD using matched logistic regression analysis. In unadjusted models, levels of six HDL proteins (APOA1, APOA4, APOC3, LCAT, PON1, and PON3) significantly associated with incident CVD. No significant associations were found for HDL-C. In the fully adjusted model for clinical confounders and lipid levels, we observed an inverse association between levels of PON1, PON3, and LCAT in HDL and incident CVD. Odds ratios (per 1-SD) were 0.38 (0.18-0.97, P=0.042), 0.42 (0.20-0.92, P=0.031), and 0.30 (0.11-0.83, P=0.020) for PON1, PON3, and LCAT, respectively. APOA4 remained associated with incident CVD in CKD patients in models adjusted for clinical confounders and lipid levels but lost significance with the addition of CRP and proteinuria in the model. In conclusion, levels of four HDL proteins, PON1, PON3, LCAT, and APOA4, were inversely associated with incident CVD events in CKD subjects. Our observations indicate that HDL’s protein cargo but not HDL-C levels can serve as a marker—and perhaps mediator—for elevated CVD risk in CKD patients.