Advances in image-guided surgery have led to minimally-invasive, high-precision procedures that increase the efficacy of treatment, minimize surgical complications, and reduce patient recovery time. A recent advance in intraoperative 3D imaging includes cone-beam CT (CBCT) implemented on a mobile C-arm. This paper investigates the effect of the number and configuration of fiducials on target registration error (TRE) and identifies fiducial configurations that minimize TRE for rigid point-based registration in CBCT-guided head and neck surgery. Best configurations were those that minimized the distance between the centroid of fiducials and the surgical target while maximizing fiducial separation (distance from principal axes). Configurations with as few as 4 fiducials could be identified that minimized TRE (e.g., TRE < 0.3 mm for the pituitary, cochlea, and nasion), with more fiducials (6 or more) providing improved TRE uniformity throughout the volume of clinical interest. If possible, fiducials affixed to the skin or cranium (e.g., 4-6 markers) should include a majority about the target (to minimize centroid-to-target distance) with others at a distance (to maximize separation). A greater number of fiducials distributed evenly can provide low, uniform TRE for all targets - e.g., 8 markers, TRE ∼0.2-0.6 mm throughout the volume of interest. Such work helps guide the implementation of C-arm CBCT in head and neck surgery in a manner that maximizes surgical precision and exploits intraoperative image guidance to its full potential.