A major problem in the treatment of patients with breast cancer is resistance to chemotherapy. Inevitably, this adversely affects the prognosis of many patients with breast cancer, shortening both their survival and affecting their quality of life. There is a growing body of evidence to support a role for DNA mismatch repair in sensitivity of cells to chemotherapy. Recent work in a small, retrospective study has shown that neoadjuvant chemotherapy results in a significant reduction in expression of one of the major mismatch repair proteins, MLH1 and that loss of MLH1 expression is strongly associated with poor disease-free survival. Two important mechanisms behind loss of mismatch repair protein expression are thought to be methylation of mismatch repair gene promoter regions and allelic imbalance. Further studies have also suggested a possible role for allelic shift, as characterised by microsatellite instability. In this study, the change in expression of potential markers for chemotherapy resistance in breast cancer following chemotherapy was investigated and the results correlated with disease-free survival. Tumour samples taken pre-and post-neoadjuvant chemotherapy were collected from a group of patients participating in an international, prospective, randomised chemotherapy trial in patients with primary breast cancer, in which patients received either adriamycin and cyclophosphamide (AC) or adriamycin and docetaxel (AD). The aims were to validate the findings in a previous retrospective study, which demonstrated the clinical importance of loss of MLH1 expression following primary chemotherapy and also to investigate the potential importance of loss of expression of the proteins MSH2, p53, Ki67, PGP, Bax and Bcl-2. This study confirmed a statistically significant reduction in MLH1 immunohistochemistry (IHC) score after chemotherapy (p=0.003, n=55). A statistically significant loss of MSH2 intensity staining and overall immunohistochemistry score (p=0.013, n=30) was also found in the cohort of patients treated with AC. Furthermore, there was a statistically significant loss of percentage staining, intensity staining and overall immunohistochemistry score of Ki67 in both groups (p=0.002, n=29 and p=0.002, n=25 respectively).