The activities of nuclear receptors (NRs), modulated by coregulators, have been found to play increasingly important roles in the development and progression of colorectal cancer (CRC). The Notch signalling pathway is a key driver in CRC, and factors that regulate both these pathways present opportunities for novel cross-talk and enhanced CRC tumor inhibition. SLIRP is an SRA-binding protein that represses ER and AR activity in hormone-dependent cancer, however, its role in CRC is unknown. In a well-studied CRC tissue microarray of 953 patients, we found SLIRP is a tumor suppressor with reduced expression in primary CRC biopsies from lymph node positive disease (OR 0.49, p<0.0001) and its expression was associated with a higher eight year survival (HR 0.66, p=0.001). SLIRP correlated inversely with MSI-H, COX-2 and vascular and lymphatic invasion, and positively with elevated β-catenin, SFRP4, P53 and MLH1 expression.High tumor levels of SLIRP mRNA also correlated with reduced relapse in CRC patients (RR 0.39, p<0.05). Functionally, in a range of CRC cells, SLIRP was a potent SRA-dependent repressor of both retinoic acid receptor α (RARα) and Notch signalling, downregulating multiple downstream targets, including HES1, SOX9, NOTCH2, NOTCH3, NFKB1 and LMO2. Depletion of SLIRP or SRA from CRC cells, produced markedly divergent effects on recruitment of RARα and SOX9 to the HES1 promoter in ChIP assays. In addition, SLIRP depleted CRC cells were also more invasive in matrigel assays and resistant to chemotherapy. Taken together, these data indicate that SLIRP is a tumor suppressor in human CRC, participates in SRA-dependent NR-Notch signalling cross-talk by potently suppressing the RARα and HES1 pathways, and suggests a potential role for SLIRP as both a biomarker and therapeutic target in this disease.