Measurements of tumor apparent diffusion coefficient (ADC), volume and diameter in assessing the response of patients with locally advanced breast cancer (LABC) (n = 56) undergoing neoadjuvant chemotherapy (NACT) at four time periods (before treatment and after three cycles of NACT) were carried out at 1.5 T using diffusion-weighted imaging (DWI) and MRI. Ten benign tumors and 15 controls were also investigated. The MR tumor response was compared with the clinical response. Mean ADC before treatment of malignant breast tissue was significantly lower than that of controls, disease-free contralateral tissue of the patients, and benign lesions, and gradually increased during the course of NACT. Analysis of the percentage change in ADC, volume and diameter after each cycle of NACT between clinical responders and non-responders showed that the change in ADC after the first cycle was statistically significant compared with volume and diameter, indicating its potential in assessing early response. After the third cycle, the sensitivity for differentiating responders from non-responders was 89% for volume and diameter and 68% for ADC, and the respective specificities were 50%, 70% and 100%. A sensitivity of 84% (specificity of 60% with an accuracy of 76%) was achieved when all three variables were taken together to predict the response. A cut-off value of ADC was also calculated using receiver operator characteristics analysis to discriminate between normal, benign and malignant breast tissue. Similarly, a cut-off value for ADC, volume and diameter was obtained after the second and third cycles of NACT to predict tumor response. The results show that ADC is more useful for predicting early tumor response to NACT than morphological variables, suggesting its potential in effective treatment management.