The objective of this study was to assess the predictive value of fatigue for work disability on medical grounds within the framework of a large prospective cohort study. Analyses were carried out on the data of 10 927 employees with a follow up of 32 months. We found that fatigue, as measured with the Checklist Individual Strength, was a strong predictor of subsequent permanent work disability. The for age, gender, presence of a chronic medical condition, and educational level adjusted relative risks were, for the 2nd, 3rd, and 4th fatigue score quartile against the first, respectively: 2.17 (1.17-4.03), 3.30 (1.67-6.52), and 12.8 (5.14-32.1).