We examined potentially modifiable lifestyle factors as possible risk factors for the onset of fatigue and psychological distress after 1-year follow-up among 8833 employees who participated in the prospective Maastricht Cohort Study of "Fatigue at Work." Results showed, even after adjustment for demographics, presence of disease, other lifestyle factors, psychosocial work characteristics, and psychological distress, that overweight (body mass index, 25 to 29.9) and being physically inactive during leisure time were strongly related to onset of fatigue in men, whereas underweight (body mass index, < 18.5) in women increased the risk for future fatigue. In addition, the study suggests some differential effects of lifestyle factors in the onset of psychological distress. Certainly, these modifiable factors can be targeted in interventions, either on an individual or group level, to prevent or at least reduce the risk of developing fatigue and psychological distress in the working population.