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Introduction The development and progression of hepatocellular carcinoma (HCC) is a multistage process involving the deregulation of genes that are crucial to cellular processes. Multiple risk factors are correlated with HCC. MicroRNA is differentially expressed in the development of different types of malignancies, including hepatic malignancy. Single nucleotide polymorphisms (SNPs) are the most common sequence variation in the human genome. SNPs in miRNAs may affect transcription, processing, or target recognition and result in malignant disease. The aim of the study was to determine the association between microRNA gene polymorphisms and the development of HCC in Egyptian patients. Material and methods This study included 200 individuals who were matched in age and sex. Tumour staging was done using the BCLC staging system. Quantification and genotyping of microRNA were performed. Results Among the 200 patients, 2 groups were described: group I included 90 HCC patients with a male majority (72.2%), and group II comprised 110 controls. Three microRNA SNPs were assayed in both patients and controls. There was a significant association between rs10061133 miR-499b and the risk of HCC. The genotypes GG or G allele were significantly associated with an increased risk of HCC (GG: OR = 2.91, 95% CI: 1.23–4.22, p = 0.013; G allele: OR = 1.79, 95% CI: 1.12–2.15, p = 0.026) compared with the genotype of AA or AG or A allele. Conclusions There is an association between the miRNA SNPs and the susceptibility to HCC, to explore some roles and mechanisms of SNPs within miRNAs in the occurrence and development of HCC.