Purpose: The purpose of this work was to evaluate whether GTV volume regression is an appropriate surrogate for treatment response during concurrent chemo-radiation therapy in locally advanced head and neck cancer. The change in GTV volume during and after fractionated treatment was correlated with clinical outcome. Methods: We used a deformable image registration algorithm to register conventional CT images to weekly CBCT images. The image registration field was used to project GTV contours from the planning CT to the weekly CBCT images. We calculated GTV volume at different time points of the fractionated treatment for 29 patients. Patients were clinically classified as CR (complete response), PR (partial response) and NR (no response) by PET exam and clinical evaluation performed 3–4 months after the completion of therapy. The PR and the NR categories were pooled into one called NCR (non-complete response). The initial GTV volume, final absolute GTV volume, early relative volume and final relative volume as well as a radiobiological parameter obtained by fitting the volume regression curves to a radiobiological model, were studied for correlation with outcome. Results: Of the four volume quantities studied, only the early volume regression showed a mean value with statistically significant difference between CR and NCR patients: 0.83±0.0.03 for CR and 0.95±0.04 for NCR (p=0.02). The radiobiological parameter had a mean of 0.86±0.03 for CR and 0.93±0.03 (p=0.03) for NCR. Conclusions: We studied volume regression in head and neck cancer patients by registering the planning CT and the weekly CBCT images. We found that while the final volume of the tumor is not a good predictor of clinical outcome, early relative volume (at about 3 weeks) showed a statistically significant difference between the CR and NCR groups. This result suggests that early volume regression could be a predictor for clinical outcome.