Objective: To assess whether CFS-like caseness (meeting the criteria for chronic fatigue syndrome (CFS)) predicts work status in the long term. Methods: Prospective study in a sample of fatigued employees absent from work. Data were collected at baseline and four years later, and included CFS-like caseness and work status (inactive work status and full work incapacity). Results: CFS-like cases at baseline were three times more likely to be unable to work at follow up than fatigued employees who did not meet CFS criteria at baseline (ORs 3-3.3). These associations grew even stronger when demographic and clinical confounders were controlled for (ORs 3.4-4.4). Conclusion: A CFS-like status (compared to non-CFS fatigue) proved to be a strong predictor of an inactive work status and full work incapacity in the long term. Since little is known about effective interventions that prevent absenteeism and work incapacity or facilitate return to work in subjects with chronic fatigue, there is a great need for powerful early interventions that restore or preserve the ability to work, especially for workers who meet criteria for CFS.