Using data from a national wound-specific electronic medical record (WoundExpert, Net Health, Pittsburgh, PA), we compared the effectiveness of a bilayered living cellular construct (BLCC) and an acellular porcine small intestine submucosa collagen dressing (SIS) for the treatment of venous leg ulcer. Data from 1,489 patients with 1,801 refractory venous leg ulcers (as defined by failure to have >40% reduction in size in the 4 weeks prior to treatment) with surface areas between 1 and 150 cm2 in size, treated between July 2009 and July 2012 at 158 wound care facilities across the US were analyzed. Patient baseline demographics and wound characteristics were comparable between groups. Kaplan-Meier–derived estimates of wound closure for BLCC (1,451 wounds) was significantly greater (p = 0.01, log-rank test) by weeks 12 (31% vs. 26%), 24 (50% vs. 41%), and 36 (61% vs. 46%), respectively, compared with SIS (350 wounds). BLCC treatment reduced the median time to wound closure by 44%, achieving healing 19 weeks sooner (24 vs. 43 weeks, p = 0.01, log-rank test). Treatment with BLCC increased the probability of healing by 29% compared with porcine SIS dressing (hazard ratio = 1.29 [95% confidence interval 1.06, 1.56], p = 0.01).