This study evaluated the efficacy and tolerability of an autologous tissue-engineered graft--a 2-step HYAFF autograft--in the treatment of diabetic foot ulcers compared with standard care. In all, 180 patients with dorsal or plantar diabetic foot ulcers (unhealed for ≥1 month) were randomized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks (n = 90; treatment group) or nonadherent paraffin gauze (n = 90; control group). Efficacy and adverse events were assessed weekly for 12 weeks, at 20 weeks, and at 18 months. The primary efficacy outcome was complete ulcer healing at 12 weeks. Wound debridement, adequate pressure relief, and infection control were provided to both groups. At 12 weeks, complete ulcer healing was similar in both groups (24% of treated vs 21% controls). A 50% reduction in ulcer area was achieved significantly faster in the treatment group (mean 40 vs 50 days; P = .018). Weekly percentage ulcer reduction was consistently higher in the treatment group. At 20 weeks, ulcer healing was achieved in 50% of the treated group as compared with 43% of controls. Dorsal ulcers had a 2.17-fold better chance of wound healing per unit time following autograft treatment (P = .047). In a subgroup with hard-to-heal ulcers, there was a 3.65-fold better chance of wound healing following autograft treatment of dorsal ulcers (P = .035). Adverse events were similar in both groups. The study results demonstrated the potential of this bioengineered substitutes to manage hard-to-heal dorsal foot ulcers.