The morphological features of neoplastic cells, combined with a stromal reaction, determine the presence of cancer at the microscopic level. Malignant tumours arise through a series of genetic alterations, but these do not entirely explain invasive and metastatic behaviour and correlate only weakly with morphological changes. In order to understand the relationship between the morphology of cancer tissue, gene expression, and clinical behaviour, a study of radiation-induced mucinous rectal carcinoma was performed. Short-term radiotherapy of rectal carcinoma results in an increased incidence of mucinous carcinoma. A cohort of rectal carcinomas (n = 1304), from patients who participated in a randomized radiotherapy trial, was evaluated for the presence and amount of a mucinous component. The results were compared with data from the pre-irradiation biopsies and revealed the presence of two distinct classes of mucinous carcinoma in the radiotherapy group, namely pre-existing (un-induced; n = 24) and induced mucinous carcinoma (n = 29). Clinical data, pathological parameters, and immunohistochemical data from these patients and their tumours showed that induced mucinous carcinomas were more comparable to typical adenocarcinomas than to pre-existing mucinous carcinomas. The prognosis of patients with induced mucinous carcinoma was significantly better than that of patients with pre-existing mucinous carcinomas (91.2% versus 39.3% recurrence-free interval at 2 years, p = 0.02). Gene expression profiles of the different groups of mucinous carcinomas and adenocarcinomas were analysed using Affymetrix Human Cancer Chips. Surprisingly, despite the difference in prognosis, the expression profile of radiation-induced mucinous carcinomas was very closely related to that of their un-induced counterparts. It is shown in the present study that radiation therapy of rectal cancer leads within a few days to substantial changes in both morphology and expression profile. However, the morphology of the pre-therapy biopsy predicts patient survival far better than post-therapy expression profiles. It is concluded that tumour morphology equates to expression profile, but that external factors might influence both, leading to sub-optimal prognostication.