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Spinal cord injury (SCI) creates a complex pathology, characterized by low levels of habitual physical activity and an increased risk of cardiometabolic disease. This study aimed to assess the effect of a moderate-intensity upper-body exercise training intervention on biomarkers of cardiometabolic component risks, adipose tissue metabolism, and cardiorespiratory fitness in persons with SCI.Twenty-one inactive men and women with chronic (>1 yr) SCI (all paraplegic injuries) 47 ± 8 yr of age (mean ± SD) were randomly allocated to either a 6-wk prescribed home-based exercise intervention (INT; n = 13) or control group (CON; n = 8). Participants assigned to the exercise group completed 4 × 45-min moderate-intensity (60%–65% peak oxygen uptake (V˙O2peak)) arm-crank exercise sessions per week. At baseline and follow-up, fasted and postload blood samples (collected during oral glucose tolerance tests) were obtained to measure metabolic regulation and biomarkers of cardiovascular disease. Abdominal subcutaneous adipose tissue biopsies were also obtained, and cardiorespiratory fitness was assessed.Compared with CON, INT significantly decreased (P = 0.04) serum fasting insulin (Δ, 3.1 ± 10.7 pmol·L−1 for CON and −12.7 ± 18.7 pmol·L−1 for INT) and homeostasis model assessment of insulin resistance (HOMA2-IR; Δ, 0.06 ± 0.20 for CON and −0.23 ± 0.36 for INT). The exercise group also increased V˙O2peak (Δ, 3.4 mL·kg−1·min−1; P ≤ 0.001). Adipose tissue metabolism, composite insulin sensitivity index (C-ISIMatsuda), and other cardiovascular disease risk biomarkers were not different between groups.Moderate-intensity upper-body exercise improved aspects of metabolic regulation and cardiorespiratory fitness. Changes in fasting insulin and HOMA2-IR, but not C-ISIMatsuda, suggest improved hepatic but not peripheral insulin sensitivity after 6 wk of exercise training in persons with chronic paraplegia.