OBJECTIVE: Little is known about psychological distress as a risk factor for the onset of long-term sickness absence and even less about the influence of fatigue in this relationship. METHODS: We examined the relationship between psychological distress and the onset of long-term sickness absence during 18 months of follow-up while considering fatigue. Analyses were based on 6403 employees participating in the Maastricht Cohort Study. RESULTS: Psychological distress was related to the onset of long-term sickness absence (women relative risk 1.45, 95% confidence interval = 1.23-1.72; men 1.33, 1.21-1.46). Adjustment for fatigue weakened the associations, particularly in women. Caseness analyses revealed different effects of psychological distress and fatigue in the onset of long-term sickness absence in men and women. CONCLUSION: The findings underline the need for interventions aiming at psychological distress and, depending on the gender, also at fatigue, to reduce the risk of long-term sickness absence. [ABSTRACT FROM AUTHOR]