STUDY DESIGN: Prospective, multicenter, randomized, and controlled Investigational Device Exemption clinical trial. OBJECTIVE: To compare the clinical safety and effectiveness of the selectively constrained SECURE-C (Globus Medical, Audubon, PA) Cervical Artificial Disc to anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Cervical total disc replacement has been developed as an alternative to ACDF by allowing segmental motion. Current cervical total disc replacement designs incorporate constrained and unconstrained metal-on-metal or metal-on-polymer articulating designs with various means of fixation. METHODS: A total of 380 patients from 18 investigational sites were prospectively enrolled in the study. Patients were randomized, treated surgically, and evaluated postoperatively at 6 weeks, 3 months, 6 months, 12 months, and 24 months. Clinical outcomes include overall success, visual analogue scale pain (right arm, left arm, and neck), neck disability index, neurological status, Short Form 36 (SF-36) Health Status Survey questionnaires, range of motion, and adverse events. Bayesian statistical methods were used to analyze the outcomes. RESULTS: Overall success results demonstrated statistical superiority of the randomized SECURE-C group compared with the randomized ACDF group at 24 months, with a posterior probability of 100% using the protocol-specified criteria and 98.1% using Food and Drug Administration-defined criteria. At 24 months postoperatively, SECURE-C demonstrated clinically significant improvement in pain and function in terms of neck disability index, visual analogue scale, and 36-Item Short Form Health Survey. At 24 months, the percentage of patients experiencing secondary surgical interventions at the index level was statistically lower for the SECURE-C group (2.5%) than the ACDF group (9.7%). At 24 months, 84.6% of as-treated SECURE-C patients were range-of-motion successes. Satisfaction was high among SECURE-C patients. CONCLUSION: The selectively constrained SECURE-C Cervical Artificial Disc is as safe and effective as the standard of care, an anterior cervical discectomy and fusion. SECURE-C is statistically superior in terms of overall success, index-level subsequent surgical procedures, and patient satisfaction, making it an attractive surgical option for patients with symptomatic cervical disc disease. LEVEL OF EVIDENCE: 1.