The relationship between fatigue and common infections was further explored, as part of a 3 year prospective cohort study on Fatigue at Work. The current study is based on seven successive questionnaires, covering the first 2 years of follow-up. The overall response at baseline was 45% (n = 12,140). On T1 10,592 (87.2% compared to baseline response) employees returned the questionnaire. For T2, T3, T4, T5 and T6, 10,270 (84.6%), 9655 (79.5%), 8956 (73.8%), 8692 (71.6%) and 8070 (66.5%) employees respectively returned the questionnaire. Self-administered questionnaires were used to determine the level of fatigue with the Checklist Individual Strength (CIS) and the occurrence of common cold, flu-like illness and gastroenteritis. Regression analysis using generalized estimated equations (GEE) were used for data analysis. We found a cross-sectional relationship between fatigue and the infections flu-like illness and gastroenteritis, and a longitudinal relationship between an infection as a predictor of fatigue. For fatigue as a predictor of an infection, we found odds ratios (ORs) of 1.35 (confidence interval (CI) 1.28-1.42) for flu-like illness and 1.33 (CI: 1.25-1.42) for gastroenteritis. The highest incidence of infections was found among employees who reported high fatigue levels on two successive occasions. The increased incidence of infections, is regarded as a substantial effect of fatigue because it is associated with significant absenteeism from work and leads to discomfort.