PTTG1-binding factor (PBF) is an oestrogen-regulated proto-oncogene that is overexpressed in thyroid, breast and pituitary tumours. The precise role of PBF in tumourigenesis, however, has not been established, nor whether it is also an aetiological factor in non-endocrine cancer. In this study, we investigated PBF function in established colorectal cells and human tumours. Specific binding was evident between the tumour suppressor p53 and both endogenous and exogenous PBF in HCT116 cells. Half-life studies also showed that PBF overexpression significantly decreased p53 stability in HCT116 cells (P<0.01). In keeping with this, greater ubiquitination of p53 was detected in PBF-transfected HCT116 cells, with no effect on p53 transcription. To gain further insight we examined p53 expression and mutational status in 15 matched normal and cancer human colorectal specimens. Western blotting showed that the majority of colorectal tumours (14/15) had increased PBF, with a mean ~6-fold induction compared to normal tissue (P<0.0001). p53 mutations were identified in eight colorectal tumours, of which seven had highly stabilized p53. Tumours with mutated p53 were associated with high PBF expression, whereas those with wild-type p53 and high PBF expression had lower p53 (P<0.05). In addition, PBF expression was significantly higher (P<0.05) in colorectal tumours with extramural vascular invasion (EMVI), an independent predictor of recurrence and poorer overall survival. Despite being oestrogen-regulated, PBF expression was not significantly different between males and females (P=0.15). Our findings suggest that PBF’s role in cell transformation most likely reflects its interaction with p53. This is the first study to demonstrate PBF overexpression in colorectal cancer, implying a role for PBF as a novel etiological marker in colorectal tumourigenesis, and revealing that PBF may also be involved in non-endocrine tumours.