Background & Aims: No specific microbiome in patients with hepatocellular carcinoma (HCC) has been reported to date. Our aim was to compare gut microbiome found in cirrhotic patients with and without HCC. Methods: From 407 patients with Child Pugh A/B cirrhosis prospectively followed, 25 with HCC (cases) were matched with 25 without HCC (wo-HCC) in a 1:1 ratio according to age, gender, etiology, Child Pugh and severity of portal hypertension. In addition 25 healthy subjects were also compared. Faecal stool samples were collected noninvasively, aliquoted for DNA extraction and sequenced for the V3-V4 region of the microbial 16S rDNA (Illumina MiSeq Platform). Results: Cases and controls baseline characteristics were: age 64 ± 8 years, 88% males, body mass index (BMI) 28 ± 4 kg/m2, hepatitis C virus infection 26%, Child Pugh A/B 74% and 26%, respectively. Barcelona Clinic Liver Cancer stages in HCC patients were 0 (n=2), A (n=12), B (n=5) and C (n=6). A significant different microbiome was observed in HCC cases vs controls. Patients with HCC had lower quantities of genus Prevotella, Fusobacterium and family Leuconostocaccaceae among others and an elevated proportion of genus Bifidobacterium, Eggerthella, Haemophilus, family Erysipelotrichaceae and phylum Tenericutes when compared to controls without HCC. This pattern has been associated with an inflammatory milieu with a putative increased activation of NOD-like receptor signalling pathways. Conclusions: A different pattern of microbiome in cirrhotic patients with HCC was observed. This pattern previously linked to inflammation, should be further explored as a novel risk factor for HCC development.