Objective Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. We aim to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC). Design We analysed 772 plasmas from 173 patients with HCC collected at the time of diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154) and during follow-up (n=116). For controls, 56 plasmas from patients with chronic liver disease without HCC were analysed. All samples were analysed for cell free DNA (cfDNA) concentration, and for mutations in TERT promoter, CTNNB1 , TP53 , PIK3CA and NFE2L2 by sequencing and droplet-based digital PCR. Results were compared with 232 corresponding tumour samples. Results In patients with active HCC, 40.2% of the ctDNA was mutated vs 14.6% in patients with inactive HCC and 1.8% in controls (p<0.001). In active HCC, we identified 27.5% of mutations in TERT promoter, 21.3% in TP53 , 13.1% in CTNNB1 , 0.4% in PIK3CA and 0.2% in NFE2L2, most of the times similar to those identified in the corresponding tumour. CtDNA mutation rate increased with advanced tumour stages (p<0.001). In 103 patients treated by percutaneous ablation, the presence and number of mutations in the ctDNA before treatment were associated with higher risk of death (p=0.001) and recurrence (p<0.001). Interestingly, cfDNA concentration and detectable mutations increased 24 hours after a locoregional treatment. Among 356 plasmas collected in 53 patients treated by systemic treatments, we detected mutations at baseline in 60.4% of the cases. In patients treated by atezolizumab-bevacizumab, persistence of mutation in ctDNA was associated with radiological progression (63.6% vs 36.4% for disappearance, p=0.019). In two patients progressing under systemic treatments, we detected the occurrence of mutations in CTNNB1 in the plasma that was subclonal in the tumour for one patient and not detectable in the tumour for the other one. Conclusion ctDNA offers dynamic information reflecting tumour biology. It represents a non-invasive tool useful to guide HCC clinical management.