Although approximately 50% of patients with non-invasive (Ta) papillary transitional cell carcinoma show no recurrence of their disease, current histopathological approaches cannot distinguish this sub-group from those patients in whom the disease will recur. In this 5 year retrospective study, we have shown that cytokeratin 20 (CK20) was expressed in 19 of 29 (65.5%) of non-invasive papillary tumours of grades 1 or 2. CK20 expression patterns were predictive of disease non-recurrence in a sub-group of eight patients, representing 51.7% of patients with non-recurrent disease. In normal bladder mucosa, CK20 expression was restricted to the terminally-differentiated superficial cell. In eight CK20-positive tumours which showed no recurrence at 5 years, CK20 expression was either restricted to, or most intense in, the luminal cells of the papillae. This pattern of expression was not seen in any of the 15 tumours from the recurrent group. Disruption of normal CK20 expression was highly significantly correlated with recurrent tumours. These results suggest that changes in the expression of differentiation-associated antigens, such as CK20, may be useful in predicting benign versus malignant behaviour and may, therefore, be useful in defining treatment strategies.