Background: Hepatocellular carcinoma (HCC) is one of the most important sanitary problems for its prevalence and poor prognosis. To date, no information is available on the prognostic value of the ov-serpin SERPINB3, detected in primary liver cancer but not in normal liver. The aim of the study was to analyse SERPINB3 expression in liver cancer in relation with molecular signatures of poor prognosis and with clinical outcome. Methods: Liver tumours of 97 patients were analysed in parallel for SERPINB3, TGF-beta and beta-catenin. In a subgroup of 67 patients with adequate clinical follow-up, the correlation of molecular findings with clinical outcome was also carried out. Results: High SERPINB3 levels were detectable in 22% of the patients. A significant correlation of this serpin with TGF-beta at transcription and protein level was observed, whereas for beta-catenin a strong correlation was found only at post-transcription level. These findings were in agreement with transcriptome data meta-analysis, showing accumulation of SERPINB3 in the poor-prognosis subclass (S1). High levels of this serpin were significantly associated with early tumour recurrence and high SERPINB3 was the only variable significantly associated with time to recurrence at multivariate analysis. Conclusions: SERPINB3 is overexpressed in the subset of the most aggressive HCCs.