Complex, full-thickness soft tissue defects secondary to large burns, trauma and war-related injuries continue to challenge reconstructive surgeons. To achieve positive surgical outcomes in these patient populations, novel approaches are needed to restore the functional, protective and aesthetic properties of skin. Herein, we provide the first report describing the staged use of a dermal regenerate template (DRT) with a spray-on epidermal regenerative modality (spray skin) in addition to autologous split-thickness skin grafting (STSG) in non-burn trauma and compare these results with those of patients treated with DRT and STSG alone. A pilot study was performed to evaluate whether the use of spray skin technology (ReCell, Avita Medical) as an adjunct to DRT (Integra, Integra Lifesciences) and autologous skin grafting in the treatment of patients with large full-thickness soft tissue losses impacts donor site burden as well as recipient and donor site re-epithelialization. In this retrospective study, two patients who were treated with DRT and STSG alone (control group) were compared with two patients who were treated with DRT and spray skin/STSG in combination (experimental group). The mechanisms of injury, total defect and treatment sizes, time to complete re-epithelialization, lengths of follow-up, outcomes and complications were reviewed. Our group observed that using a DRT in conjunction with spray skin/STSG can reduce donor site burden and decrease time to complete healing. It can also permit greater or larger meshing ratios, while aiding in improved re-pigmentation when compared with similar wounds treated with a DRT and autologous skin grafting alone. Copyright © 2017 John Wiley & Sons, Ltd.