Objective: To investigate the difference in clinical efficacy between zero-profile interbody fusion (ROI-C) and stand-alone interbody cage combined with cage-titanium plate construct for patient with two-segment skipped cervical spondylosis who received the anterior cervical discectomy and fusion (ACDF) surgical strategies. Methods: The clinical data of 62 patients with two-segment skipped cervical spondylosis who underwent surgical treatment in the First Affiliated Hospital of Zhengzhou University from June 2017 to June 2020 were retrospectively analyzed, included 38 males and 24 females, aged (53.3±8.5) years. Thirty-three cases were treated with ROI-C (ROI-C group), and 29 cases with stand-alone interbody cage combined with cage-titanium plate construct (cage+titanium plate group). The following parameters, including operation time, intraoperative blood loss, dysphagia Bazaz grade, Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) of pain, neck disability index (NDI), average intervertebral height of operated segments, C2-7 Cobb angle, and related complications, were compared between the two groups. Results: The patients were followed up for (28±5) months (16-34 months). The operation time of ROI-C group was (127.6±34.2) min, which was shorter than that in cage+titanium plate group [(157.1±43.9) min, P=0.004]. The scores of JOA and VAS in both ROI-C group and cage+titanium plate group were significantly improved 3 months after operation when compared with those before operation, and there was no significant difference between the two groups (all P>0.05). The average intervertebral space height of fusion segment in ROI-C group was (6.02±1.03) mm before operation, it was improved to (8.38±1.47) mm at 3 months after operation, (8.16±1.40) mm at 12 months after operation, and it was (6.24±1.05) mm, (8.58±1.18) mm and (7.87±0.73) mm in cage+titanium plate group, respectively, and there was no significant difference between the two groups at each time point (all P>0.05). The Cobb angle of cervical vertebrae in ROI-C group was 10.5°±6.8° before operation, improved to 19.2°±9.0° at 3 months after operation, 18.2°±5.8° at 12 months after operation, and it was 10.9°±4.6°, 18.5°±7.8°, 17.1°±5.2° in cage+titanium plate group, respectively, and there was no significant difference between the two groups at each time point (all P>0.05). The incidence of postoperative dysphagia was 9.1%(3/33) in the ROI-C group and 37.9%(11/29) in the cage+titanium plate group, and the difference was statistically significant (P=0.007). Conclusions: Both ROI-C and stand-alone interbody cage combined with cage-titanium plate construct can achieve good results for two-segment skipped cervical spondylosis. However, ROI-C is more advantageous in shortening the operation time and reducing early postoperative dysphagia.