Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3α,5α-tetrahydroprogesterone; 3α,5α-THP) and isopregnanolone (3β,5α-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased (P< 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3α,5α-THP and pregnanolone (3α,5β-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3β,5α-THP, 3β,5β-THP and 3α,5α-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3α,5α-THP and 3α,5β-THP were found to be significantly higher in patients with fatigue (P < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3α,5α-THP and 3α,5β-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood–brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.