Background: Negative pressure wound therapy (NPWT) is becoming routine for the preparation of wounds prior to grafting for wound closure. With this purpose, we have been using both foam and gauze-based NPWT obtaining similar proportions of closed wounds and observing less pliable scar tissue on the foam-treated patients. The aim of this study was to compare this two different fillers and to identify if there are different indications for their use according to anatomical areas in relation to the type of granulation and scar tissue obtained. Methods: Both foam and gauze patients were compared in terms of depth and wound location, patients' age, and comorbidities. All foam patients were treated at 125 mmHg for an average of 25 days before skin grafting, while gauze patients were treated at 80 mmHg for an average of 21 days before skin grafting. Biopsies of granulation and scar tissues were taken and stained with hematoxylin-eosin and Masson's trichrome stainings, investigating vascular endothelial growth factor (VEGF) and metalloproteinase (MMP). An ultrasound analysis of the closed wounds was also conducted. Results: Histological, immunohistochemical, and ultrasonographical results after gauze-based NPWT showed a minor tissue thickness and disorganization and less sclerotic components. Conclusions: These results support the hypothesis that different fillers generate different scar tissues. The choice of the filler to apply negative pressure should be dictated by the anatomical areas affected by the lesion. Level of Evidence: Level IV, therapeutic study. [ABSTRACT FROM AUTHOR]