BACKGROUND: Home parenteral nutrition (HPN) is a life-saving therapy for patients with diseases that preclude adequate oral or enteral food intake. HPN has a large impact on daily life. Many patients suffer from fatigue and depression, and they experience limits in social activities. This all contributes to a lower quality of life. PURPOSE: Fatigue is the most frequently mentioned problem in Dutch HPN patients. Therefore, we studied the prevalence, course and predictors of fatigue in these patients. METHODS: Patients completed questionnaires at baseline and follow-up (12 months later). Measurements included fatigue, depression, functional impairment, social support, self-efficacy, coping, anxiety and acceptance. Laboratory measures, including total bilirubin, creatinine, albumin and haemoglobin levels, were obtained from the medical records. Descriptive statistics, correlations and linear regression analysis were performed. RESULTS: The response rate was 71% (n = 75). Sixty-five per cent of the patients were severely fatigued (n = 49). Eighty-nine per cent experienced persistent fatigue. Baseline fatigue predicted 57% of the variance of fatigue at follow-up, and avoidance was responsible for 3% of the variance. No significant correlations between fatigue and laboratory measures were found. A cross-sectional analysis showed that 46% of the variance of fatigue was explained by functional impairment, self-efficacy and depression. CONCLUSION: Severe fatigue is a persistent problem for HPN patients. Baseline fatigue was the strongest predictor of fatigue at follow-up. Functional impairment, self-efficacy and depression are strongly related to fatigue. Early recognition and treatment of fatigue are important.