Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. By representational difference analysis (RDA), a novel human gene designated SVH, up-regulated in the clinical HCC sample, was identified. The deduced SVH protein consisted of 343 amino acids with a transmembrane domain and an armadillo repeat. Northern blot revealed that SVH was expressed in most human adult tissues. Four variants of SVH, SVH-A, -B, -C, and -D, resulting from alternative splicing in the coding region of the SVH transcript, were observed and were all localized in endoplasmic reticulum (ER). Up-regulation of SVH-B, but not the other variants, was evident in about 60% (28 of 46) of HCC samples, detected by quantitative real-time PCR. Human liver cell line QSG-7701, transfected with SVH-B, acquired an accelerated growth rate and tumorigenicity in nude mice, whereas inhibition of SVH-B in hepatoma cell line BEL-7404, using antisense oligodeoxynucleotides, induced apoptosis. It is suggested that the splicing variants of SVH have distinct biological functions, and SVH-B may play an important role in hepatocarcinogenesis.