To improve the setup reproducibility of neck curvature using real-time optical surface imaging (OSI) guidance on 2 regions of interest (ROIs) to infer cervical spine (c-spine) curvature for surface-guided radiotherapy (SGRT) of head-and-neck (HN) and c-spine cancer. A novel SGRT setup approach was designed to reproduce neck curvature with 2 ROIs: upper-chest ROI and open-face ROI. It was hypothesized that the neck curvature could be reproduced if both ROIs were aligned within ±3 mm/2˚ tolerance. This was tested prospectively in 7 volunteers using real-time 3D-OSI guidance and lateral 2D-photography verification after the 3D and 2D references were captured from the initial conventional setup. Real-time SGRT was performed to align chest-ROI and face-ROI, and the longitudinal distance between them was adjustable using a head-support slider. Verification of neck curvature anteriorly and posteriorly was achieved by overlaying edge-extracted lateral pictures. Retrospectively, the relationship between anterior surface and spinal canal alignment was checked in 11 patients using their simulation CT (simCT) and setup cone-beam CT (CBCT). After the anterior surface was rigidly aligned, the spinal canal alignment was checked and quantified using the mean-distance-to-agreement (MDA) and DICE similarity index, and surface-to-spine correlation was calculated. The reproducibility of neck curvatures using the 2xROI SGRT setup is verified and the mean neck-outline-matching difference is within ±2 mm in lateral photographic overlays. The chest-ROI alignment takes 110 ± 58 s and the face-ROI takes 60 ± 35 s. When the anterior body surface is aligned (MDA = 1.1 ± 0.6 mm, DICE = 0.96 ± 0.02,) the internal spinal canal is also aligned (MDA = 1.0 ± 0.3 mm, DICE = 0.84 ± 0.04) in 11 patients. The surface-to-spine correlation is c = 0.90 (MDA) and c = 0.85 (DICE). This study demonstrates the feasibility of the novel 2-ROI SGRT setup technique to achieve reproducible neck and c-spine curvature regardless of neck visibility and availability as ROI. Staff training is needed to adopt this unconventional SGRT technique to improve patient setup.