Uterine Leiomyomas (UL) are the most common tumors in women of reproductive age, which leads to approximately 200,000 hysterectomies annually in the United States. Although over 95% of UL tumors are benign, they destroy the function of the uterus and cause abnormal uterine bleeding, anemia, pelvic pain, and recurrent pregnancy loss. Activation of the WNT pathway is well established as a driver of cell proliferation and tumorigenesis. In UL, cytogenetic deletion studies have shown that the chromosomal region 7q22.3 is associated with UL in around 40% of patients. Furthermore, the tumor suppressor HBP1, an inhibitor of Wnt signaling, is one of the 15 genes located by mapping these deletions. Because HBP1, a repressor of Wnt signaling, lies in this minimally deleted region, we hypothesized that decreased HBP1 expression may contribute to WNT signaling in UL. Using patient samples obtained from hysterectomy, we showed the protein levels of beta-catenin, the signature signal in activation of Wnt signaling, increased in leiomyoma compared to that in myometrium. Furthermore, Axin II mRNA, a common target gene of Wnt signaling, also increased in fibroids. These results suggest activation of WNT signaling is common in fibroid tumors. Furthermore, HBP1 also decreased in approximately 50% of leiomyomas, consistent with the deletion studies. To identify whether decreased HBP1 defined a unique sub-type of fibroid tumor, we undertook an unbiased screen of UL patients using RNAseq and bioinformatics analysis to identify global and HBP1-dependent changes in UL. As predicted by previous published work, an ESR1-activated proliferation gene expression signature was common in all leiomyoma samples. In tumors with normal HBP1 levels, cell cycle and GPCR signaling, cholesterol biosynthesis related gene signatures were active compared to HBP1 low leiomyomas. In contrast, in the HBP1-low tumors, WNT signaling, mRNA metabolism and translation signatures were present, consistent with qPCR and Western Blotting results. In conclusion, these data demonstrate that the WNT signaling pathway, and in particular the Wnt repressor HBP1, may play a critical role in pathogenesis of leiomyoma.