Introduction: Alterations in the glycosylation pattern of immunoglobulin G (IgG) play a key role in the transition from healthy to diseased tissue, and have been related to inflammation, immune function, and cardiovascular disease (CVD) risk factors.Hypothesis: We hypothesized that IgG glycosylation patterns are associated with the risk of developing CVD events.Methods: IgG glycosylation profiles were measured using ultra-performance liquid chromatography on baseline plasma samples from two nested CVD case-control studies within the JUPITER (NCT00239681; Npairs=162; discovery) and the TNT (Npairs=367, validation) randomized trials. In both cohorts, we used conditional logistic regression adjusted for age, sex, statin, race, LDLC, smoking, hypertension, BMI, HDLC, triglycerides, and hs-CRP to examine the association of 24 IgG glycan peaks (IgG-GPs) with incident CVD events. In the controls sample, we performed Spearman correlation between IgG-GPs and hs-CRP, a biomarker of inflammation.Results: After adjusting for CVD risk factors and correcting for multiple testing (overall FDR<.05), one agalactosylated fucosylated glycan (IgG-GP4) was positively associated with CVD risk (odds ratio [OR]=1.4, 95%CI= 1.1; 1.9), while three digalactosylated (IgG-GPs 12, 13, and 14), and one monosialylated glycan (IgG-GP 16) were negatively associated with CVD risk in JUPITER (OR ranging from 0.7 to 0.8, 95%CI=0.5; 1.0). The results replicated in TNT (Figure 1). IGG-GP4 positively correlated with hs-CRP, while an inverse non-significant correlation, was observed for IGG-GPs 12, 13, and 14 with hsCRP (Figure 1).Conclusions: Certain glycosylation traits were associated with risk of incident CVD independent of clinical risk factors and statin therapy. Specifically, one agalactosylated fucosylated glycan was positively associated with CVD risk, while digalactosylated and sialylated glycans were inversely associated with CVD risk in two independent cohorts.