OBJECTIVES: The objective of this study was to assess the comparative effectiveness of enzymatic debridement with clostridial collagenase ointment (CCO) plus sharp debridement compared to sharp debridement alone (SD) for the management of stage IV pressure ulcers (PU) in the hospital outpatient department setting. METHODS: Electronic medical records on PU were taken from the U.S. Wound Registry from 2007-2013 and used for the comparative effectiveness analysis. A propensity score matching method was used to adjust for selection bias and to test for treatment effects between the CCO and SD cohorts. RESULTS: Using sharp debridement current procedural terminology codes and propensity score matching 337 CCO and 336 SD stage IV PU were identified and used in the analysis. After matching, both groups were statistically similar with respect to patient age, PU surface area and PU age. The average patient ages were 66 years (±19) in the CCO group and 64 (±19) in the SD group. The average stage IV PU wound sizes were 16cm (±23) in the CCO group versus 18cm(±29) in the SD group. The average stage IV PU ages were 355 days (±412) in the CCO group versus 501(±743) days in the SD group. The proportion of wounds closed at 1 year or 2 years was 2 times greater in the CCO group compared to the SD group (p<0.0001). Kaplan-Meier analysis showed that the average time to stage IV PU closure was significantly faster in the CCO group at 456 days versus 589 days in the SD group (p<0.0001). CONCLUSIONS: CCO as an adjunct therapy coupled with sharp debridement yielded better clinical outcomes and facilitated faster closure rates for stage IV PU relative to sharp debridement alone. Healthcare providers should consider CCO an effective adjunctive therapy to sharp debridement when treating PU in the hospital outpatient department setting.