OBJECTIVE: To estimate the prevalence of fatigue and accompanying lost labor costs (work absence and reduced performance while at work) among US workers. METHODS: Cross-sectional study using data from the Caremark American Productivity Audit, a national random-digit-dial telephone survey of the US population designed to measure the relation between health and work productivity. The sample comprised 28,902 employed adults participating in the audit between August 1, 2001, and July 30, 2002. A total of 11,719 workers with fatigue were identified. A comparison group consisted of a gender- and age-matched random sample (1:1) of workers without fatigue. Outcome measures included fatigue prevalence, lost productive time (LPT) due to fatigue and LPT for any health-related reason expressed in hours and converted to dollars. RESULTS: The estimated two-week period prevalence of fatigue in the U.S. workforce was 37.9%. Overall, 9.2% of workers with fatigue reported LPT due to fatigue in the previous two weeks. This group lost 4.1 productive hours per week, on average, and cost employers an estimated $330 million per year; 83.9% of the LPT cost was due to reduced performance while at work. Comparing LPT for any health-related reason between workers with and without fatigue, workers with fatigue cost US employers an estimated $136.4 billion per year in health-related LPT, an annual excess of $101.0 billion. Excess health-related LPT is primarily explained by the mean threefold increase in the percent of workers reporting LPT due to other health conditions when fatigue is present. CONCLUSIONS: Fatigue is prevalent in the US workforce and can impair work ability. When present as a secondary symptom to other health conditions, fatigue is associated with significantly more LPT due to those conditions.