Based on the hypothesis that both ATM and MRE11 are integral to the detection of DNA damage and subsequent intracellular signalling following radiotherapy, and hence their deficiency would equate to increased radiosensitivity, we established a two-marker panel of ATM and MRE11 expression by binary regression analysis of tumor samples and normal tissues. Subsequent analyses showed greater association with general clinicopathologic parameters than either marker alone, as well as yielding a ROC-AUC value of 0.745 in predicting poor histological tumour regression (i.e. TRG 3) following radiotherapy. The latter was superior to using ATM (0.618) or MRE11 (0.711) alone. Furthermore, in both the neoadjuvant radiotherapy sub-cohort and the overall cohort, the combined ATM/MRE11 expression levels correlated with clinical survival outcomes. Thus these markers, when used together, related to both early (histological tumour regression) and late (clinical survival) response to neoadjuvant therapy in rectal cancers. These findings support our hypothesis and are also consistent with the fact that inhibitors of ATM and the MRN complex have been shown to have potential as radiosensitizing agents .