Recently, a novel liver-related putative tumor suppressor (LPTS), which has a growth inhibitory function in the hepatocellular carcinoma (HCC) cell line, has been identified at chromosome 8p23. To determine the relationship of the LPTS with the development or progression of HCC, we analyzed the genetic alterations and the expression pattern of the LPTS gene in a series of 80 HCCs, six dysplastic nodules, and eight large regenerating nodules, determining the genomic structures. We identified a total of seven exons, of which two were alternative, and three LPTS isoforms, short (LPTS-S), medium (LPTS-M), and long-sizes (LPTS-L). In the genetic alteration study of the LPTS gene, no mutation was detected in the large regenerating nodules, dysplastic nodules, and HCC, whereas ten (34.5%) of 29 informative cases at one or more intragenic polymorphic sites showed loss of heterozygosity (LOH). Interestingly, LOH was identified only in HCC samples with hepatitis B virus (HBV) infection and the frequency of LOH was not statistically related with histologic grade and clinical stage, suggesting that allelic loss of the LPTS gene may occur as an early event in the development of HCC, especially in the cases with HBV infection.