Background. Persistent fatigue is strongly associated with functional status and can lead to absenteeism and work disability. Despite several prognostic studies on chronic fatigue, little attention has been paid to occupational outcomes. Method. A total of 127 fatigued employees on sick leave were followed-up after 4 years to determine long-term predictors of work disability, fatigue caseness and chronic fatigue syndrome (CFS)-like caseness. Measures included fatigue, physical functioning, illness attributions, psychological problems and emotional exhaustion. Results. Thirty-three participants (26%) were receiving work disability benefits at the 4-year follow-up. Older age and lower levels of physical functioning predicted work disability. Weaker psychological attributions and lower levels of physical functioning were predictors of fatigue caseness. CFS-like caseness was predicted by female gender and lower levels of physical functioning. Self-reported physical functioning remained a strong and statistically significant determinant of work disability [odds ratio (OR) 0·45, 95% confidence interval (CI) 0·24-0·87] and CFS-like caseness (OR 0·20, 95% CI 0·09-0·43) after controlling for confounders. Conclusions. This study suggests that physical functioning plays an important role in the persistence of fatigue complaints and work disability in employees on sick leave. The course of fatigue is a complex process, and exploring temporal relationships between fatigue, functional status and work status in future research could provide valuable information for the improvement of fatigue management.