Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, causing about 1 million deaths annually. Patients with HCC usually reported multiple concurrent symptoms. The purpose of this multivariate study was to explore whether multiple concurrent symptoms are clustered into groups of symptoms and to explore the effect of symptom clusters on the quality of life (QOL) in patients with HCC. A sample of 180 patients with HCC at a medical center in Korea was recruited. Patients completed a demographic questionnaire, a Symptom Checklist, the Hospital Anxiety and Depression Scale, and the Functional Assessment of Cancer Therapy-Hepatobiliary. Factor analysis was used to identify symptom clusters based on the severity of patients' symptom experiences. Four symptom clusters were identified: pain-appetite, fatigue related, gastrointestinal, and itching-constipation. Two patient subgroups were identified through cluster analysis: high- and low-symptom group. Patients in the high-symptom group had significantly poorer functional status and poorer QOL in all the domains, with the exception of social well-being. The differences between the 2 patient subgroups were not only statistically but also clinically significant. Patients in the high-symptom group were also statistically and clinically anxious and depressed. Further research is needed to explore whether compositions of symptom cluster phenotypes vary over time and whether the associations of symptom clusters with QOL and mood are changing along the disease and treatment trajectory as well as symptom status.