This study evaluated the factors that affect the resting energy expenditure (REE) and nutritional status of hemodialysis patients, and to assess any differences with healthy subjects. This was an observational case-control study. This study took place at the Hemodialysis Units of the Laikon General Hospital and 401 General Military Hospital (Athens, Greece). Twenty-five patients undergoing hemodialysis and 23 controls were recruited. Controls were healthy volunteers with no history of diseases or medication use. Patients with active infectious or inflammatory disease were excluded. We measured REE using indirect calorimetry. Body composition as measured by Bioelectrical Impedance Analysis (BIA), anthropometry, and biochemical parameters were assessed in both groups. Adjusted or unadjusted for muscle mass, REE was compared between the two groups. Multiple linear regression analysis was used to study independent determinants of REE. Patients had no clinical signs of malnutrition. Resting energy expenditure was not different between the two groups, but REE adjusted for muscle mass was significanlty higher in hemodialysis patients. There were no differences in body composition, with the exception of muscle mass. Patients had lower muscle mass than controls, as determined by duration of disease. The only significant determinant of REE was muscle mass. Patients had a higher REE adjusted for muscle mass than did controls, implying that they might be at a catabolic stage, and at risk of malnutrition. These findings indicate the need for determining body composition and for nutritional assessment and support in hemodialysis patients, even without indications of malnutrition.