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Simple Summary: Hepatocellular carcinoma (HCC) has the highest incidence and mortality rate in the Asian population. However, it is unclear how ethnic genetic variability affects this. Our research shows that hsa-miR-100-5p, a miRNA associated with HCC prognosis, improves prognosis in Asians. In contrast, Polo-like kinase 1 (PLK1), inhibited by hsa-miR-100-5p, worsens HCC prognosis in Asians. A single-nucleotide polymorphism (SNP) named rs27770, located in the 3′UTR of PLK1, has a significantly higher frequency of the G allele in the East Asian population. The A>G change in rs27770 affects the PLK1 mRNA secondary structure and alters the hsa-miR-100-5p/PLK1 interaction by creating an additional seedless binding site. This could make hsa-miR-100-5p more favorable for HCC prognosis in the Asian population. Our findings could help explain why the Asian population is more susceptible to HCC. Hepatocellular carcinoma (HCC) has the highest incidence and mortality in the Asian population, and race is an independent risk factor affecting survival time in liver cancer. Micro RNAs (miRNAs) are remarkably dysregulated in HCC and closely associated with HCC prognosis. Recent studies show that genetic variability between ethnic groups may result in differences in the specificity of HCC miRNA biomarkers. Here, we reveal a high expression level of hsa-miR-100-5p, an HCC prognosis-related miRNA, which improves HCC prognosis in the Asian Population with Polo-like kinase 1 (PLK1) variant rs27770A>G. In this study, we discovered that hsa-miR-100-5p was downregulated in various HCC cell lines. While mimics transient transfection and mouse liver cancer model confirmed the interaction between hsa-miR-100-5p and PLK1, a stratified analysis based on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data suggest both low hsa-miR-100-5p expression level and high PLK1 expression level associated with poor HCC prognosis, especially in the Asian population. According to the 1000 Genomes Project database, the SNP rs27770 located in 3′UTR of PLK1 had a significantly higher G allele frequency in the East Asian population. Bioinformatics analysis suggested that rs27770 A>G affects PLK1 mRNA secondary structure and alters the hsa-miR-100-5p/PLK1 interaction by forming an additional seedless binding site. This racial variation caused PLK1 to be more vulnerable to hsa-miR-100-5p inhibition, resulting in hsa-miR-100-5p being more favorable for HCC prognosis in the Asian population. [ABSTRACT FROM AUTHOR]