Background/Objectives: Individuals with a spinal cord injury (SCI) experience reductions in lower-extremity muscle mass and increased fatty-infiltration of skeletal muscle, predisposing them to an increased risk of specific secondary health conditions. To date, few investigations have prospectively examined changes in muscle in the chronic stage of SCI. Peripheral quantitative computed tomography (pQCT) is an imaging technique capable of measuring lower-extremity skeletal muscle cross-sectional area (CSA) and muscle density, the latter is a surrogate measure of muscle fatty infiltration. The purpose of this project was to a) determine the magnitude of muscle CSA and muscle density reduction in a chronic-SCI population with diverse impairments; b) identify demographic and injury characteristics associated with muscle CSA and density status; and c) determine if muscle CSA and muscle density change over a two-year period following chronic-paralysis and if so, what factors are associated with the changes. Materials and Methods: Seventy individuals [50/20 m/f, mean (± SD) age 48.9 ± 11.5 years; duration of injury 15.5 ± 10.0 years] with chronic (>2 years post-injury) SCI (C1-T12, AIS A-D) were enrolled in a two-year cohort study. Muscle CSA and muscle density values were calculated from pQCT scans of the 66%-site of the calf obtained at baseline and two follow-up visits separated by one year. Possible correlates of muscle CSA and density selected a priori included: gender, age, height, weight, waist circumference, age at injury, level of injury, injury duration, leg spasm frequency and severity scale score (SFSS), ISNCSCI calf-muscle lower-extremity motor score (cLEMS), wheelchair use, serum vitamin D level, and physical activity level. Dependent t-tests were used to compare muscle CSA and muscle density values of participants with complete and incomplete-SCI to age, gender, and height matched able-bodied controls. Multiple linear regression models were used to determine correlates of muscle CSA and muscle density. Repeated measures analysis of variance (rANOVA) were used to examine change in muscle CSA and density over the two-year study duration and multiple linear regression models were created to determine correlates of muscle CSA and density change from baseline. Results: Individuals with motor-complete SCI had a 45% reduction in muscle CSA and a 32% reduction in muscle density relative to controls. Participants with motor-incomplete SCI had a 17% reduction in muscle CSA and a 14% reduction in muscle density relative to controls. A reduced height, waist circumference, cLEMS, and wheelchair use were associated with a smaller muscle CSA in the best-fitting regression model (R2 = 0.66; p<0.0001). In the best-fitting regression model for muscle density, increased age, a lower cLEMS, reduced SFSS, fewer minutes of daily vigorous physical activity, and wheelchair use were associated with a lower muscle density (R2= 0.37; p<0.001). A high degree of individual variability in muscle CSA change (mean ± SD: -1.9 ± 6.2cm2; range: -22.6 to 8.5 cm2) and muscle density change (mean ± SD: -1.2 ± 3.28mg/cc; range: -8.6 to 6.4 mg/cc) was observed in those with both complete and incomplete SCI over the two-year study duration. rANOVA indicated a significant reduction in both muscle CSA and density after controlling for individual variability. A greater waist circumference at baseline was weakly associated with a reduction in muscle CSA (R2 = 0.14, p<0.05), and a lower weight and waist circumference at baseline were associated with a reduction in muscle density (R2 = 0.26, p < 0.001 and R2 = 0.20, p < 0.01, respectively). Conclusion: Age, completeness of injury, spasticity, physical activity participation, and ambulation ability were identified as potential clinical predictors of muscle status in individuals with chronic-SCI. Muscle CSA and density does not reach a “steady-state” after chronic-SCI. Further investigation is needed to determine the mechanisms responsible muscle CSA and density change in order to prevent continued reductions after chronic-SCI.