Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The lack of effective therapeutic options for advanced stage HCCs combined with an increasing incidence rate calls for the identification of early stage HCC molecular markers. SH2 Domain Containing 4A (SH2D4A) gene maps to human chromosome 8p21.3 and encodes for SH(2)A. The chromosomal region containing SH2D4A is frequently lost in colorectal, lung and HCC cancers. Our study aimed to investigate SH2D4A involvement in HCC pathogenesis combining mRNA expression, protein and clinical data. Transcriptome analysis performed on 37 HCC needle biopsies (matched with their corresponding non-neoplastic parenchyma) and five normal liver donor samples revealed that SH2D4A is downregulated in HCC. Results were confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR), 25 out of 37 (67.6%) fresh frozen samples showed SH2D4A downregulation (p=0.026). Furthermore, combining qRT-PCR and immunohistochemistry data we demonstrated a direct correlation between SH2D4A mRNA and SH(2)A protein levels. The analysis of a tissue microarray (TMA) containing 336 specimens confirmed that SH(2)A is frequently reduced in HCC (56.8%) as well as in cirrhotic nodules (50.5%) compared to normal liver samples (31.1%). To conclude, our study revealed that SH2D4A is frequently downregulated in HCC samples thus corroborating its putative role as a tumour suppressor gene. In addition, we provide new evidence for SH2D4A involvement in HCC pathogenesis demonstrating for the first time its deregulation in cirrhotic nodules.