Background: The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial showed no incremental benefit of extended-release niacin (ERN) therapy added to simvastatin in subjects with cardiovascular disease (CVD). Objectives: To examine the effects of ERN treatment on lipoprotein particles and GlycA, a new marker of systemic inflammation, and their relations with incident CVD events including mortality. Methods: GlycA and very low–density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle subclasses were quantified by nuclear magnetic resonance spectroscopy using available stored baseline (n = 2754) and 1-year in-trial (n = 2581) samples. Associations with CVD events and all-cause mortality were assessed using multivariable Cox proportional hazards regression adjusted for age, sex, diabetes, treatment assignment, and lipoproteins. Results: Compared to placebo, ERN treatment lowered very low–density lipoprotein and LDL and increased HDL particle concentrations, increased LDL and HDL particle sizes (all P <.0001), but did not affect GlycA. Baseline and in-trial GlycA levels were associated with increased risk of CVD events: hazard ratio (HR) per SD increment, 1.17 (95% confidence interval [CI], 1.06–1.28) and 1.13 (1.02–1.26), respectively. However, none of the lipoprotein particle classes or subclasses was associated with incident CVD. By contrast, all-cause mortality was significantly associated with both GlycA (baseline HR: 1.46 [1.22–1.75]; in-trial HR: 1.41 [1.24–1.60]) and low levels of small HDL particles (baseline HR: 0.69 [0.56–0.86]; in-trial HR: 0.69 [0.56–0.86]). Conclusions: This Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial post hoc substudy indicates that inflammation, as indexed by GlycA, is unaffected by ERN treatment but is significantly associated with the residual risk of CVD and death in patients treated to low levels of LDL cholesterol.