Nuclear receptors (NRs), whose activities are modulated by coregulators, and the Notch signaling pathway, play key roles in colorectal cancer (CRC). Factors that regulate both NR and Notch activity may mediate novel cross-talk and provide opportunities for CRC therapy. SLIRP (steroid receptor RNA activator (SRA)-binding protein) represses NR activity, however its role in CRC is unknown. To investigate its potential importance in CRC, its expression in two CRC cohorts was assessed. Elevated SLIRP expression correlated with reduced risk of relapse (RR 0.39, p<0.05) and higher eight year CRC patient survival (HR 0.66, p<0.01) while lower levels in primary biopsies was associated with more frequent lymph node positive disease (OR 0.49, p<0.0001). Functionally, in a range of CRC lines, SLIRP was a SRA-dependent repressor of both retinoic acid receptor α (RARα) and Notch signaling, downregulating multiple downstream targets, including HES1, SOX9, NOTCH2, 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. Notably, there was no difference in AOM/DSS induced tumour formation between SLIRP KO and wild type mice however SLIRP-depleted CRC cells are more invasive in vitro. Taken together, these data indicate SLIRP may function as a tumor suppressor in CRC and participates in SRA-dependent NR-Notch signaling cross-talk that impacts progression rather than initiation of CRC.