Sphingolipid metabolism serves important role in regulating sphingolipid biology, and it is implicated in various diseases including hepatocellular carcinoma (HCC). HCC is the most common histologic subtype of primary liver cancer and is associated with significant mortality worldwide. The development of genomic profiling analysis has allowed the identification of novel prognostic factors and treatment targets for the disease. The purpose of the present study was to determine the mRNA expression and prognostic significance of sphingolipid metabolism-related genes in HCC. Gene expression RNAseq data retrieved from The Cancer Genome Atlas Liver Cancer (TCGA LIHC) datasets were used for bioinformatic analysis. The results revealed that sphingolipid metabolism-related genes were dysregulated in HCC tissues compared with normal solid tissues (NST). The Student’s t-test and analysis of genes with ≥2-fold differences in mRNA expression levels revealed that HPGD, ST8SIA3, LPAR1, NAAA, and GALC were significantly downregulated, whereas GBA, SLC26A10, LASS1, and B4GALNT1 were significantly upregulated in HCC tissues compared with NST. Kaplan-Meier survival analyses demonstrated that higher mRNA expression levels of B4GALNT1 and GBA were associated with a poor prognosis in HCC. Therefore, B4GALNT1 and GBA may serve as novel prognostic indicators and treatment targets in HCC.