Uterine fibroids (UF) are the most common noncancerous gynecologic tumors presented in reproductive-age women. It is well known that UF disproportionately affects African American (AA) women, being more prevalent and severe in them compared with European American (EA) population. To date, we understand little about the underlying causes of the ethnic disparity. This work aimed to identify transcriptomic signatures and regulated pathways involved in at-risk myometrium in the context of UF, in AA and EA women, using RNA-seq approach. Myometrial tissue from uteri without UF (MyoN), myometrium adjacent to UF (MyoF), and UF (n=3 AA, n=3 EA, each group) from consented women were collected via the University of Illinois at Chicago Medical Center. Whole-genome RNA-seq was performed in the tissues to determine global gene expression profiles. RNA-Seq data was aligned using HISAT2 to the human genome build UCSC hg38. Gene expression quantification was achieved using FEATURECOUNTS against the GENCODE gene model. Differential gene expression was evaluated using the R package EdgeR, and expression was further normalized using the R package RUVr (FC >1.5x and FDR-adjusted p-value <0.05). Enriched pathways were assessed via the over-representation (OR) method (as implemented by MSigDB) using the hypergeometric distribution and the Reactome compendium (FDR-adjusted p-value<0.05). Transcriptomic analysis demonstrated that 2594 genes (2029 up, 565 down) and 1960 (143 up, 1817 down) were differentially expressed when compared AA-MyoF vs AA-MyoN and EA-MyoF vs EA-MyoN, respectively. However, when comparing MyoF vs MyoN after combining AA and EA populations data, we found just 309 differentially expressed genes (108 up, 201 down). Interestingly, when overlapped the MyoF vs MyoN differentially expressed genes by ethnicity we observed that only 32 genes presented the same change direction (i.e., up in both ethnicities, and vice versa), while 665 showed opposite change direction (i.e., up in AA and down in EA, and vice versa). The OR analysis of enriched pathways showed that when compared MyoF and MyoN in each population the signaling involved is different, for example Developmental Biology in AA and Signaling by GPCR in EA. In contrast, when we performed OR analysis between UF vs MyoN and UF vs MyoF gene sets in AA and AE populations, we found that both present the extracellular matrix signaling among the top enriched pathways, suggesting that UF pathology develop is similar during the tumor growth phase. Our results demonstrate a unique transcriptomic signature in at- risk myometrium related to the ethnicity, suggesting the important mechanism underlying the increased prevalence and burden in AA women with UF. This study demonstrated that the comparison of the transcriptomics of at-risk myometrium in comparison with normal myometrium give us the possibility to identify pathways that may explain the observed higher UF risk and prevalence in AA women. In addition, our analysis points out the importance of distinguishing the ethnicity groups in UF research field.