Proline-, glutamic acid-, and leukine-rich protein (PELP1) is a novel co-regulatory protein that modulates genomic and non genomic actions of estrogen receptors. Nuclear receptor co-repressor (NCoR) represses estrogen-receptor-dependent transcription. PELP1 and NCoR expression was evaluated in tissue sections from 107 formalin-fixed, paraffin-embedded colectomy specimens. Normal mucosa and adenomas were also evaluated in 77 and 29 cases, respectively. PELP1 was expressed in a dot-like pattern in the nuclei of epithelial and stromal cells. Statistical analysis revealed an increase in PELP1 expression in myofibroblasts from normal mucosa through adenomas to carcinomas. NCoR was expressed in the nuclei and the cytoplasm of epithelial cells. Nuclear expression was more common in normal mucosa, whereas cytoplasmic expression was higher in malignant epithelial cells. Additionally, NCoR was expressed in the cytoplasm of cancer-associated myofibroblasts, but was rarely noted in myofibroblasts of normal mucosa or adenomas. Cytoplasmic expression of NCoR in epithelial cells correlated with better disease-free and overall survival on univariate analysis and was an independent prognostic marker for disease-free survival on multivariate analysis. These findings suggest that deregulation of co-regulators expression in both epithelial cells and myofibroblasts may contribute to the initiation and progression of colorectal carcinoma.