In Amyotrophic Lateral Sclerosis (ALS) spinal cord (SC) showed a moderate increase in FDG uptake with respect to healthy subjects. The main aim of our study is to integrate the information concerning the divergent behavior of SC with skeletal muscle metabolism improving the informative potential of 18F-fluoro-2-deoxy-glucose (FDG) PET/CT imaging regarding specific pathophysiological mechanisms underlying ALS progression. We analyzed 50 ALS patients with spinal onset consecutively submitted to FDG PET/CT imaging. Obtained data were compared to the corresponding findings in 36 age and sex-matched controls. A computational method was used to extract psoas volume and attenuation coefficient from CT images. Psoas volume was normalized for patient ideal body weight (IBW). In co-registered PET images, FDG accumulation was defined by average normalized standardized uptake value (N-SUV). Average Hounsfield values (AVH) in the psoas were similar in patients and controls (39±8 AHV vs 39±11 AHV, respectively, p=ns). By contrast, ALS was associated with a significant reduction in psoas volume normalized for IBW (8.8±2.9 mL/Kg IBW vs 10.3±2.7 mL/Kg IBW, respectively, p<0.05). More interestingly, N-SUV was significantly higher in patients than in controls (0.44±0.19 vs 0.29±0.09; p<0.001). These SUV values predicted overall survival rate at Kaplan-Meyer analysis (p<0.05) with a predictive power that was confirmed by univariate as well as by multivariate Cox analysis (p<0.02). ALS is therefore associated with a psoas reduction in volume and increase in FDG uptake. The intensity of FDG uptake within this muscular district is related to disease aggressiveness.