Background: Tamoxifen (TAM) is an effective hormone therapy that reduces the risk of cancer recurrence. According to evidence, TAM contributes to the alterations of genetic variants background and plays a role in the effectiveness of treatments via alteration of the genetic variants. The effects of TAM on genomic features were investigated in the current study by discovering genetic variants and finding the answer to the following question: “Is there any association between the alterations of genetic variants under TAM consumption and an effective treatment process?” Materials and Methods: Whole-transcriptome (RNA-seq) dataset from four investigations including 10 TAM-treated samples and 9 untreated samples as the control groups were derived from European Bioinformatics Institute (EBI). Using the process of variants calling, the differential genetic variants between and gene ontology enrichment analysis were detected by CLC Genomics Workbench (12). Results: Current study reported about 5.8 million genetic variants. The outcomes of the chi-square test showed that distributions of genetic variants between control and treated samples were significant (p<0.05). The genetic variants comparison between the control and TAM-treated samples indicated that there were 67 differential genetic variants. Gene ontology enrichment analysis indicated that differential genetic variants were associated with several tumor suppressors and oncogenes including IL6ST, GEN1, FNTA. HSPA5, NSMCE2, and DDX11.Conclusion: Most of the candidate genes with different genetic variants had dual roles as oncogenes or tumor suppressors. Therefore, it can be argued that TAM does not play a significant role in an effective treatment through alteration of the genetic variants. In other words, it cannot be concluded that the TAM therapy-resulted alterations of genetic variants play a positive or negative role in the treatment process.