Evidence exists demonstrating that infection with hepatitis C virus impairs health-related quality of life, but less is known about the effect of fatigue, a common symptom, on everyday life. The psychometric properties of the fatigue severity scale (FSS) were explored to determine suitability as an outcome measure in clinical trials. The FSS includes nine items developed to measure disabling fatigue and a visual analog scale (VAS) to measure overall fatigue. Using baseline data from three clinical trials (n = 1225) involving chronic hepatitis C patients, scaling and psychometric characteristics of the FSS were assessed. The SF-36 was also used in the trials. Item response theory analysis demonstrated that the FSS items can be placed along a single homogenous domain, fatigue. Internal consistency reliability was 0.94. Test-retest reliability was 0.82 for the total score and 0.80 for the VAS. The total score and the VAS were significantly correlated with the SF-36 vitality subscale (r = -0.76 and r = -0.76 respectively). Correlations with other SF-36 subscales were moderate (r = -0.46 to r = -0.67, all p < 0.0001). In summary, the FSS possesses good psychometric properties.