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We sought to examine the relationship between frailty and health-related quality of life as evaluated using the 36-item Short-Form Health Survey (SF-36) questionnaire in Japanese chronic liver disease (CLD) patients (<i>n</i> = 341, 122 liver cirrhosis cases, median age = 66 years). Frailty was defined as a clinical syndrome in which three or more of the following criteria were met (frailty score 3, 4, or 5): unintentional body weight loss, self-reported exhaustion, muscle weakness (grip strength: <26 kg in men and <18 kg in women), slow walking speed (<1.0 m/s), and low physical activity. Robust (frailty score 0), prefrail (frailty score 1 or 2), and frailty were found in 108 (31.7%), 187 (54.8%), and 46 (13.5%) patients, respectively. In all eight scales of the SF-36 (physical functioning, role physical, bodily pain, general health perception, vitality, social functioning, role emotion, and mental health), and the physical component summary score and mental component summary score, each score was well stratified according to the frailty status (all <i>p</i> < 0.0001). In the multivariate analysis, age (<i>p</i> = 0.0126), physical functioning (<i>p</i> = 0.0005), and vitality (<i>p</i> = 0.0246) were independent predictors linked to the presence of frailty. In conclusion, Japanese CLD patients with frailty displayed poorer conditions, both physically and mentally.