Colorectal cancer (CRC) is the second highest cause of cancer death and the third most common malignancy. Aberrant Notch signaling in CRC promotes epithelial to mesenchymal transition, chemoresistance and metastasis. Its effects are mediated through transcription factors (TFs), in particular HES1 and HEY1, which influence COX2, NF-B and Wnt signaling. In CRC, Notch signaling can be activated by retinoic acid, through the nuclear receptor (NR) RARa and the early developmental TF SOX9, which activates HES1. Using CRC tissue microarrays (TMAs), we found that SLIRP, a nuclear receptor (NR) corepressor, is a good prognostic factor in CRC, with a tumor suppressor phenotype. High tumor SLIRP expression in a TMA cohort of 967 patients correlated with improved 5 year survival (p<0.01) and inversely with tumor stage and lymph node invasion. In two CRC cDNA microarray sets, high SLIRP mRNA expression correlated with improved disease free survival over three years following surgery (p<0.05). Here we investigated the mechanism for this clinical advantage and the hypothesis that SLIRP is a repressor Notch signaling. In human CRC cell transfection studies using luciferase (Luc) reporters, siRNA mediated depletion of SLIRP increased the activity of ligand-stimulated RAR, HES1 and SOX9 signaling, resulting in increased expression of downstream targets, including NOTCH2, NOTCH3, NFKB1, NFKB2, LMO2, HES1 and SOX9. In ChIP studies, SLIRP was recruited (with RARa) to the HES1 and SOX9 promoters. When SLIRP was depleted from the cells with siRNA, ChIP studies revealed an increase in RARa recruitment to the HES1 and SOX9 promoters, along with increased binding of SOX9 to the HES1 promoter, and a decrease in binding of HES1 to its own promoter. Further, we found that siRNA mediated SLIRP depleted CRC cells were more invasive in matrigel assays and more resistant to the standard CRC chemotherapeutic agents, 5-Fluorouracil and irinotecan. Taken together, these data suggest that SLIRP is a potent suppressor of Notch and RARa signaling in CRC and provide insight into the mechanisms by which SLIRP functions as a tumor suppressor to reduce invasion and enhance sensitivity to chemotherapy in this disease.