Purpose: With a limited overall survival (OS) of 20 months in patients diagnosed with intermediate stage hepatocellular carcinoma (HCC), the preservation of quality of life (QoL) during transarterial chemoembolization (TACE) procedures remains a primary goal. The aim of our study was to evaluate the change in QoL amongst patients undergoing repetitive TACE and to identify specific risk factors that may predict change in QoL. Methods: QoL was assessed in 82 patients undergoing at least two TACE, before and 14 days after TACE, using validated EORTC QLQ-C30 and EORTC HCC18 questionnaires. Tumour response was assessed using established response criteria. Laboratory and clinical parameters were analysed. Results: Functional scores decreased due to first TACE treatment (p < 0.01), conversely symptom scores increased significantly (p < 0.01). During repetitive TACE no statistically significant changes were observed. Higher Global Health- and Physical Functioning scores at baseline were identified as independent prognostic factors for greater decrease in QoL. Tumour response did not alter QoL at all. Furthermore higher symptom scales including pain (p = 0.00), nausea and vomiting (p = 0.00) and fever (p < 0.01 for repetitive TACE) at baseline were predictive of a significantly lesser increase of symptom severity, and a greater reduction in pain during a course of TACE. Higher C-reactive protein (CRP) at baseline and female gender were associated with a greater decrease of functional scales and increase of symptom scales. Conclusion: QoL amongst patients receiving repetitive TACE showed neither significant nor clinically relevant changes over time. Pre-treatment assessment of QoL-scores, clinical and laboratory parameters can improve patient selection for TACE whilst optimizing QoL.