The diagnosis and treatment of breast cancer are stressful, and stress may be associated with a poorer response to chemotherapy. There is a need, therefore, to develop and evaluate interventions that might enhance quality of life and, possibly, improve treatment response. The effects of relaxation combined with guided imagery (visualizing host defences destroying tumour cells) on quality of life and response to primary chemotherapy, to date, have not been adequately evaluated. Ninety-six women with newly diagnosed large or locally advanced breast cancer (T2 > 4 cm, T3, T4, or TxN2 and M0) took part in a prospective, randomized controlled trial. Patients were randomized following diagnosis to a control condition (standard care) or to the experimental condition (standard care plus relaxation training and imagery). Psychometric tests to evaluate mood and quality of life were carried out before each of the six cycles of chemotherapy and 3 weeks after cycle 6: tests of personality and coping strategy were carried out prior to cycles one and six. Clinical response to chemotherapy was evaluated after six cycles of chemotherapy using standard UICC criteria and pathological response was assessed from the tissue removed at surgery. As hypothesized, patients in the experimental group were more relaxed and easy going during the study (Mood Rating Scale). Quality of life was better in the experimental group (Global Self-assessment and Rotterdam Symptom Checklist). The intervention also reduced emotional suppression (Courtauld Emotional Control Scale). The incidence of clinically significant mood disturbance was very low and the incidence in the two groups was similar. Finally, although the groups did not differ for clinical or pathological response to chemotherapy, imagery ratings were correlated with clinical response. These simple, inexpensive and beneficial interventions should be offered to patients wishing to improve quality of life during primary chemotherapy.