Binding of specific ligands to the receptor for advanced glycation end-products (RAGE) can trigger a series of signal transductions, which leads to pathogenesis in many chronic degenerative diseases, including cancer. Alternative splicing of RAGE mRNA has resulted in many variants, including RAGE variant 1 (RAGEv1). This particular splice variant of RAGE can provide a major soluble form of RAGE in blood circulation, which can neutralize deleterious ligands, thus diminishing signaling that can lead to inflammation and pathogenesis in cancer cells. However, the molecular mechanisms involved in suppressing signaling cascades in the cells are unknown. We investigated the molecular role of the RAGEv1 isoform in modulating NF-kB and TNF-α gene expression in human hepatocellular carcinoma HepG2 cells. Transient transfection using an engineered plasmid containing the RAGEv1 gene resulted in a significant increase in normalized RAGEv1 mRNA transcripts in HepG2 cells. This finding was supported by the detection of the RAGEv1 protein, which was found in the whole-cell extracts and the cell culture media. This high degree of RAGEv1 expression significantly reduced the expression of normalized mRNA transcripts of NF-kB and TNF-α in HepG2 cells. We suggest that RAGEv1 could reduce activity of the NF-kB signaling pathway in liver cancer cells, thus providing a potential alternative therapy for the treatment of liver cancer.