Four generic [the Sickness Impact Profile (SIP-68), Short-Form Health Survey (SF-36), EuroQol instrument (EQ-5D), COOP/WONCA charts], two domain-specific health-related quality of life measures [the sexuality scale of the HIV Overview Problems Evaluating System (HOPES), Multi-dimensional Fatigue Index (MFI-20)], and a self-developed 12-item symptom index were compared in terms of feasibility, test-retest reliability, internal consistency reliability, construct validity, and known groups validity in patients with chronic liver disease. All instruments could be completed within 10 min and exhibited a good psychometric performance in patients with chronic liver disease. The SF-36 and the MFI-20 performed relatively best in terms of reliability, construct validity, and discriminative ability. The sexuality scale of the HOPES demonstrated a relatively poor performance, as the missing value rate was higher than 5%. Further research is needed into the sensitivity to important clinical changes of the instruments.