Functional imaging with tomographic near infrared diffuse optical spectroscopy (DOS) can quantitatively measure tissue parameters such as the concentration of deoxy-hemoglobin (Hb), oxy-hemoglobin (HbO2), percent water (%water), and scattering power (SP). The purpose of this study was to evaluate the correlation between DOS functional parameters with pathologic outcomes. Patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy or chemoradiotherapy were recruited to this study (n = 10). Five scans were conducted per patient: a baseline scan was taken up to 3 days prior to treatment and at 1 week, 4 weeks, 8 weeks, and after neoadjuvant treatment prior to surgery. At each scan the patient lay prone with the breast suspended between immobilization plates in optical coupling medium. Pulsed near-infrared laser light was used to scan the breast at four different wavelengths and data was used for tomographic reconstruction. Volume-of-interest (VOI) weighted tissue Hb, HbO2, %water, and SP corresponding to the tumour was calculated and compared to clinical and pathological response as determined from full mount mastectomy pathology. For all 10 patients the tumour-based VOI was significantly different than background tissue for all functional parameters (p<0.001). Five patients had a good clinical and pathologic response. Four patients were considered non-responders. One patient initially had a poor clinical response to chemotherapy but after a change in chemotherapy had a good clinical and radiographic response. Responders and non-responders were significantly different for all of the functional parameters (p<0.05) at the 4-week scan. In the 5 patients with a good response the mean drop in Hb, HbO2, %water, and SP from baseline to the 4-week scan was 70.4% (SD = 18.6), 66.5% (SD = 24.5), 59.6% (SD = 30.9), and 60.7% (SD = 29.2), respectively. In contrast, the 4 non-responders had a mean drop of 17.7% (SD = 9.8), 18.0% (SD = 20.8), 15.4% (SD = 11.7), and 12.6% (SD = 10.2), for Hb, HbO2, %water and SP, respectively. Functional imaging using tomographic diffuse optical spectroscopy parameters of Hb, HbO2, %water and SP could be used as an early detector of final clinical and pathologic tumor response. This could be evaluated in the future to assess responses and potentially adjust chemotherapy regimins.