Uncomplicated major surgery is followed by a pronounced increased feeling of fatigue extending throughout the first month in about one-third of patients. Postoperative fatigue correlates with the degree of surgical trauma but is not related to duration of general anesthesia and surgery or to preoperative nutritional status, age, or sex. Fatigue also correlates with postoperative deterioration in nutritional parameters and impaired adaptability of heart rate during exercise. Furthermore, a postoperative decrease in muscle force and endurance is related to postoperative fatigue, whereas psychological factors are of minor importance. These findings suggest postoperative fatigue to be mediated by the endocrine-metabolic response to surgery, impaired nutritional intake, or immobilization, but the relative role of these factors remains to be established. Until then, therapeutic measures against the development of postoperative fatigue should aim at reducing the surgical stress response, effective treatment of pain to facilitate mobilization, and exercise to increase postoperative nutritional intake.