BACKGROUND: Standardized mortality ratio for primary biliary cirrhosis (PBC) is 2.87. Even after accounting for liver and cancer-related deaths there is an unexplained excess mortality associated with PBC. We have assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) risk factors associated with cardiovascular mortality, in 57 PBC patients and age- and sex-matched normal controls. METHODS: HRV and BRS were measured non-invasively in subjects and controls. Beat to beat RR interval and \'Portapres\' blood pressure data were processed using power spectral analysis. Power was calculated in very low frequency (VLF), low-frequency (LF) and high-frequency (HF) bands according to international guidelines. BRS (alpha) was computed using cross-spectrum analysis. Patients also underwent fatigue severity assessment using a measure validated for use in PBC. RESULTS: PBC patients had significantly lower total HRV compared with controls (P=0.02), with the reduction occurring predominantly in the LF domain (P=0.03). BRS was also significantly reduced compared with controls (P=0.02). There were no significant differences in HRV or BRS between cirrhotic and non-cirrhotic patients. Within the PBC patient group HRV was significantly lower in fatigued than in non-fatigued patients (P<0.05). CONCLUSION: Abnormalities of HRV and BRS in PBC are not specific to advanced disease but are associated with fatigue severity. Abnormalities could be associated with increased risk of sudden cardiac death, potentially contributing to the excess mortality seen in PBC.