Context. Anorexia nervosa (AN) is an excessive form of calorie restriction (CR) associated with pathological weight loss and alterations of the immune system. However, AN patients seem to be protected from common viral infections. Objectives. To investigate the metabolic and molecular adaptations induced by sustained extreme CR in the peripheral blood mononuclear cells (PBMCs) of patients with restrictive alimentary AN. Design. Inflammatory cytokines and adipokines were measured in 15 young (age range, 15-24 years) AN female patients and 20 age-matched healthy controls. Isolated PBMCs were immunophenotyped by flow cytometry, and glycolysis and mitochondrial respiration were determined by measuring the extracellular acidification and oxygen consumption rate. Stress resistance to H2O2 and the antioxidant transcriptional profile of PBMCs and human fibroblasts incubated with sera from AN patients were also determined. Results. Compared with controls, AN patients (BMI, 15.9 +/- 0.4 kg/m(2)) had significantly fewer leucocytes, lymphocytes and NK cells, lower serum concentrations of leptin, IGF-1 and sTNFR1, and higher levels of adiponectin, sCD40L and sICAM-1 (p < 0.05). IL-1 beta, TNF alpha, and IL-6 produced by PBMC cultured with autologous serum for 48 h were significantly lower in AN patients than in controls (p < 0.01). Moreover, glycolysis and mitochondrial respiration were lower, and the antioxidant transcriptional profile was higher in the PBMCs of AN patients. Fibroblasts cultured in serum from AN patients showed a 24% increase in resistance to H2O2 damage. Conclusions. Extreme CR in AN patients is associated with a reduction in several immune cell populations, but with higher antioxidant potential, stress resistance and an anti-inflammatory status.