The prognostic importance of tumour infiltrating lymphocytes (TILs) in colorectal cancer (CRC) remains controversial. The present study was undertaken to evaluate the role of TILs as prognostic indicators and to investigate the role of transforming growth factor-beta (TGF-beta) in TIL infiltration. Immunohistochemical staining for components in the TGF-beta pathway was performed on a tissue microarray of 1420 unselected CRCs with complete clinico-pathological data. Statistical analyses were carried out on samples stratified by mismatch repair (MMR) proficiency status and TIL counts. TIL infiltration was found to correlate with multiple clinico-pathological features but was a prognostic marker only in MMR proficient CRCs. In all CRCs, findings indicative of insensitivity to TGF-beta and increased TGF-beta secretion were independent predictors of high TIL counts, suggesting that perturbations in the TGF-beta signalling pathway play an important role in the recruitment and retention of TILs within CRC epithelium.