The computational and geometric performance of Demons deformable registration techniques were investigated in the application of cone-beam CT (CBCT) for intra-operative guidance of head and neck surgery. A prototype C-arm providing CBCT images of sub-mm spatial resolution and soft-tissue contrast was used to acquire images of a cadaveric head before and after surgical intervention. Four deformable registration methods were investigated both in terms of their convergence behavior (time and number of iterations required) and registration accuracy (correlation between deformed and target images and the corresponding target registration error, TRE). Rigid registration alone exhibited a TRE of (2.6 ± 1.0) mm, compared to a TRE of (0.8 ± 0.3) mm obtained with deformable registration. A fast symmetric demons implementation was identified as the most suitable for intra-operative use in terms of speed, image quality, and accuracy. Increasing the spatial resolution of CBCT images was found to increase registration accuracy at the cost of computational expense. Intra-operative CBCT combined with deformable registration offers to overcome conventional limitations of guidance by preoperative images alone and presents an accurate method of integrating imaging and planning data in a manner that properly reflects changes in the intra-operative state.