OBJECTIVES: To assess the cost-effectiveness and economic impact of enzymatic debridement with clostridial collagenase ointment (CCO) compared with medicinal honey (MH) for pressure ulcer (PU) treatment from a US payer/Medicare perspective in the hospital outpatient department (HOPD) setting. METHODS: A budget impact analysis using Markov health state transitions was developed using a 1-week cycle length across a 1-year time period to estimate the potential economic impact (expressed in 2016 US dollars) after increasing the market share of PU patients treated with CCO. The three health states were: (1) inflammation/senescence; (2) granulation/proliferation (ie, patients achieving 100% granulation); and (3) epithelialization. Data sources included the US Wound Registry, Medicare fee schedules, and published clinical and cost studies about PU treatment. RESULTS: In the base-case analysis over a 1-year time horizon, CCO was the economically dominant strategy (ie, simultaneously conferring greater benefit at less cost). Patients treated with CCO experienced 22.7 QALWs at a cost of $6,161 over one year, while MH patients experienced 21.9 QALWs at a cost of $7,149. Patients treated with CCO achieved 11.5 granulation weeks and 6.0 epithelization weeks compared with 10.6 and 4.4 weeks for MH, respectively. The number of clinic visits was 40.1 for CCO vs 43.4 for MH, and number of debridements was 12.3 for CCO compared with 17.6 for MH. Assuming a patient population of 1000 patients, for every 1% of patients shifted from MH to CCO, a cost savings of $9883 over one year is observed by the payer. Probabilistic sensitivity analyses determined CCO to be dominant in 72% of 10,000 iterations and cost-effective in 91%, assuming a benchmark willingness-to-pay threshold of $50,000/quality-adjusted life year ($962/QALW). CONCLUSIONS: The results of these economic analyses suggest CCO is a cost-effective, economically dominant alternative to MH in the treatment of patients with PUs in the HOPD setting.