Background: Diabetic Foot Ulcers (DFUs) are associated with substantial morbidity, health care utilization, and risk of lower-extremity amputation. Advanced wound treatments such as skin substitutes are commonly used in the management of DFUs when standard wound care alone is insufficient. Recent changes in the Medicare Physician Fee Schedule (PFS) and the Outpatient Prospective Payment System (OPPS) have standardized reimbursement for skin substitutes based on surface area applied, increasing interest in healing outcomes and treatment-related costs under the payment framework. Objective: To descriptively compare published healing outcomes and estimated cost per healed DFU across selected advanced skin substitutes in the context of CMS payment policies. Methods: A descriptive comparison was conducted using published 12-week DFU healing probabilities and estimated treatment-related costs for five advanced skin substitutes: Helicoll, Grafix, Apligraf, Dermagraft, and EpiFix. Cost per healed DFU was calculated as the ratio of estimated treatment-related cost to reported healing probability. The primary effectiveness outcome was complete ulcer healing at 12 weeks. Cost assumptions were standardized using publicly available CMS reimbursement methodologies. Deterministic one-way sensitivity analyses were performed. Results: Among the reported healing probabilities ranged from approximately 0.30 to 0.62 across products, Helicoll demonstrated a favorable balance of cost and effectiveness, with an annual per-patient cost of $20,000 and a 12-week healing probability of 0.58. This resulted in a cost per healed DFU of $34,500, which was 25-40% lower than comparator products. Incremental analysis showed Helicoll has the higher reported healing probabilities and the lowest calculated cost per healed DFU among evaluated products. Conclusion: In this comparative effectiveness analysis, Helicoll provided clinically meaningful healing outcomes at substantially lower cost compared with other specific advanced skin substitutes. These findings support Helicoll as a cost-effective treatment option for DFU management.