Background: polymorphisms in different miRNAs lately are found to have potential to be biomarkers for HCC susceptibility, but the results still inconsistent. Objective: This study was conducted to explore the potential role and clinical significance of rs 10877887 polymorphisms in the promoters of let-7 family and risk of HCC susceptibility, in addition to response to doxorubicin treatment in Egyptian patients. Patients and methods: We genotyped the single nucleotide polymorphism (SNP) in 100 patients with HCC and 50 healthy controls. Analysis of the rs10877887 was done using polymerase chain reaction-restriction fragment length polymorphism assay. Results: We found that the rs 10877887 genotype distribution and allele frequency did not associated neither with increased risk of developing HCC (adjusted OR =0.7178, 95% CI, [0.4409 – 1.1687], p1=[0.1825] P>0.05) nor with the response to doxorubicin treatment (adjusted OR = 1.1874, 95% CI, 0.6683.-2.1096, P = 0.5581). Conclusion: These findings indicate that the rs10877887 CC/CT may not play a role as a risk factor for the development of HCC. Also, it cannot be used to detect the response of Egyptian patients to doxorubicin treatment.