Background: The prohormone preproenkephalin (ppE) and its derived peptides are involved in leukocyte functioning as well as in the regulation of hunger and satiety. Various abnormalities of the immune and endocrine systems have been described in states of malnutrition such as anorexia nervosa (AN). We hypothesized that ppE expression in AN patients may vary depending on the state of the disorder and the extent of malnutrition. Methods: Expression of ppE mRNA was analysed in peripheral blood mononuclear cells of 29 underweight and 29 weight-recovered patients with AN and compared to that in 29 healthy control women. The extent of malnutrition was characterized by BMI and plasma leptin. Psychological distress and eating disorder specific-psychopathology was determined with the Symptom Checklist-90-Revised and the Eating Disorders Inventory-2. Results: ppE gene expression was similar in all 3 groups and was not related to nutritional status or eating disorder symptoms. However, a significant negative correlation was found between ppE expression and obsessive-compulsive, depressive and anxious symptoms. In addition, ppE expression was higher in smokers compared to non-smokers. Conclusion:Although malnutrition and hypoleptinaemia as seen in patients with AN were not related to peripheral ppE expression, we demonstrated reduced ppE expression in patients with elevated psychological distress. Similar associations have been shown in animal models of stress. It remains speculative if psychological symptoms and/or stress may augment immune abnormalities in AN patients via a pathway that is independent of nutritional status and involves ppE.