GlycA is a new composite measure of systemic inflammation and a predictor of many inflammatory diseases. GlycA is the nuclear magnetic resonance spectroscopy-derived signal arising from glucosamine residues on acute-phase proteins. This study aimed to evaluate how exercise-based lifestyle interventions modulate GlycA in persons at risk for type 2 diabetes. GlycA, fitness, and body habitus were measured in 169 sedentary adults (45–75 years) with prediabetes randomly assigned to one of four six-month exercise-based lifestyle interventions. Interventions included exercise prescription based on the amount (energy expenditure (kcal/kg weight/week (KKW)) and intensity (%VO2peak). The groups were (1) low-amount/moderate-intensity (10KKW/50%) exercise; (2) high-amount/moderate-intensity (16KKW/50%) exercise; (3) high-amount/vigorous-intensity (16KKW/75%) exercise; and (4) a Clinical Lifestyle (combined diet plus low-amount/moderate-intensity exercise) intervention. Six months of exercise training and/or diet-reduced GlycA (mean Δ: −6.8 ± 29.2 μmol/L; p=0.006) and increased VO2peak (mean Δ: 1.98 ± 2.6 mL/kg/min; p<0.001). Further, visceral (mean Δ: −21.1 ± 36.6 cm2) and subcutaneous fat (mean Δ: −24.3 ± 41.0 cm2) were reduced, while liver density (mean Δ: +2.3 ± 6.5HU) increased, all p<0.001. When including individuals in all four interventions, GlycA reductions were associated with reductions in visceral adiposity (p<0.03). Exercise-based lifestyle interventions reduced GlycA concentrations through mechanisms related to exercise-induced modulations of visceral adiposity. This trial is registered with Clinical Trial Registration Number NCT00962962.