Background. Despite major treatment advances, diabetic foot ulcers (DFUs) remain a frequent and debilitating complication of diabetes mellitus and a major cause of significant morbidity and mortality. Objective. This study evaluates and compares clinical effectiveness of clostridial collagenase ointment (CCO) with standard care (SC) in patients with DFUs, with the goal to define best clinical criteria under which to use CCO in the DFU population. Materials and Methods. This is a pooled data analysis of 4 randomized controlled trials that compared clinical effectiveness of CCO to SC. A total of 174 adult patients with 1 target DFU each who underwent treatment with CCO (n = 88) or SC (n = 86) for 4 or 6 weeks were evaluated. Assessments included wound area reduction, wound bed status, and time to closure. Results. Statistically significant mean percentage change in wound area from baseline was numerically greater for CCO than SC at the end of study (EOS) following 6 or 8 weeks of treatment; these values were -56% and -10%, respectively, in the subgroup of plantar surface ulcers (P = .05) and wounds assessed as “low necrosis” (≤ 25% necrotic) at baseline (-64% vs. -20%). When rapidly healing ulcers were excluded from the analysis, the difference in ulcer area reduction was even greater for CCO compared with SC at EOS (-53% vs. -7%; P = .05). Conclusions. Active CCO therapy was associated with a nonstatistically greater reduction in wound size than any of the passive or mechanical SC modalities at end of treatment. This was statistically significant when used in conjunction with sharp debridement and for slow healing ulcers, larger sized wounds, or plantar surface wounds.