Quality of life is an important concern for patients with chronic liver disease. We sought to describe the frequency, severity, and associations of fatigue, in patients with primary biliary cirrhosis (PBC). We performed association testing between PBC-40 multidomain disease-specific quality of life responses and clinical findings. Three hundred twenty-seven patients from a single clinic with PBC (94% female, 92% AMA-positive) were evaluated. The average age was 57 years and average disease duration 7.2 years. Verbally reported fatigue was noted in 48% but present in the overwhelming majority on PBC-40 completion, with 44% having moderate or severe symptoms. Of those not complaining of fatigue clinically, 25% documented moderate or severe fatigue by questionnaire. Age had an inverse relationship with fatigue (P < 0.01), whereas body mass index (BMI) was positively associated (P < 0.01), as was the presence of pruritus (P < 0.001), sicca symptoms (P < 0.001), depression (P < 0.001), fibromyalgia (P < 0.004), and scleroderma (P < 0.05). For those with varices (P < 0.05) or cirrhosis clinically (P < 0.05), higher fatigue scores were noted, although those who initially presented with noncirrhotic disease had higher scores at the time of testing (P < 0.005). Fatigue was associated with greater use of prescription medication (P < 0.01), in particular for antipruritics (cholestyramine: P < 0.001; rifampin: P < 0.001), proton pump inhibitors (P < 0.002), beta-blockers (P < 0.02), and antidepressants (P < 0.001), whereas those taking calcium and vitamin D appeared less fatigued (P < 0.05). In a multivariate model, calcium and vitamin D use, BMI, stage of disease at diagnosis, as well as symptomatic fatigue or pruritus, were significant. Biochemical response to UDCA was not associated with lower fatigue scores. Conclusion: Attempts at defining the biological basis of fatigue in patients with PBC, and improving its treatment, must account for its multifactoral causes. (HEPATOLOGY 2010