Purpose: To compare clinical outcomes in patients with pressure ulcers (PUs) who were treated with enzymatic debridement using clostridial collagenase ointment (CCO) with those treated with autolytic debridement using a hydrogel dressing. Patients and methods: This prospective, randomized, blinded, single-site trial directly compared the use of CCO and hydrogel dressings for treatment of PUs in patients in a long-term care facility. Changes in wound bed scores (WBS), tissue granulation, wound surface area, and epithelialization were assessed weekly during the 6-week treatment. Effects of treatment time, treatment method, and the combination of treatment time and method on continuous outcomes were analyzed by linear regression; the effects of covariates on epithelialization were analyzed by logistic regression. Results: Overall, 27 patients completed the study; 13 patients were treated with CCO and 14 with hydrogel. Baseline demographic and clinical characteristics were similar between the treatment groups. Patients treated with CCO had a granulation rate approximately twice that of those receiving hydrogel and showed a significantly higher rate of granulation tissue formation at week 6. Treatment duration and the combination of treatment duration and method were significant predictors of granulation tissue formation. WBS improvements from baseline to week 6 were greater in patients who received CCO than in those treated with hydrogel (+4.6 units versus +2.6 units, respectively). Treatment duration and the combination of treatment duration and method were predictors of WBS improvement. Patients treated with CCO showed significant reductions in wound surface area from baseline (10.3 cm 2 ) to week 6 (2.1 cm 2 ). At week 6, epithelialization was numerically higher in patients treated with CCO than in patients treated with hydrogel. Conclusion: Long-term care facility patients with PUs who received enzymatic debridement with CCO had greater improvements in granulation tissue formation, WBS, wound surface area, and wound closure than did those treated with hydrogel.