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Background: Dysregulated erythropoietin (EPO) plasma levels may play a role in the pathophysiology of chronic liver disease (CLD) because chronic anaemia is frequently observed in patients with liver cirrhosis. We aimed to identify the factors contributing to EPO regulation in patients with CLD. Methods: Plasma EPO concentrations were correlated with clinical and laboratory parameters in 111 CLD patients and 220 healthy controls. Results: Anaemia, though generally mild, was common in CLD patients, and thrombocytopenia and previous bleeding episodes were observed in two-thirds of the patients. Plasma EPO levels were significantly elevated in CLD patients ( P < 0.001). EPO increased according to Child's stages of cirrhosis, independently of the aetiology of CLD. EPO correlated with haemoglobin ( r = -0.498, P < 0.001). Additionally, EPO independently correlated with markers of liver dysfunction, e.g. prothrombin time, albumin concentration or cholinesterase activity, and platelet count. EPO was also significantly elevated in patients with a current bleeding tendency and with prior gastrointestinal haemorrhages. EPO levels were increased in patients with impaired pulmonary function, e.g. decreased diffusion capacity, vital capacity or hyperventilation. Interestingly, plasma interleukin-6 (IL-6) concentrations positively correlated with EPO ( r = 0.277, P = 0.003), suggesting a possible mechanism of EPO upregulation in patients with CLD through IL-6 dependent pathways, e.g. binding of STAT transcription factors in the putative EPO promoter region. Conclusions: EPO is upregulated in patients with chronic liver diseases in response to anaemia, bleeding complications, impaired pulmonary function, thrombocytopenia and liver dysfunction. IL-6 dependent pathways could be involved in mediating elevated EPO levels in CLD patients. [ABSTRACT FROM AUTHOR]